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NDT Advance Access originally published online on August 25, 2007
Nephrology Dialysis Transplantation 2008 23(1):201-206; doi:10.1093/ndt/gfm572
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


The role of renal biopsy in women with kidney disease identified in pregnancy

Clara Day1, Peter Hewins1, Sarah Hildebrand1, Lumaan Sheikh2, Gabrielle Taylor1, Mark Kilby2 and Graham Lipkin1

1Dept of Nephrology, University Hospital, Birmingham NHS Foundation Trust, Edgbaston, Birmingham B15 2TH and 2Dept of Fetal Medicine, Birmingham Women's; Health Care NHS Trust, Birmingham, B15 2TG

Correspondence to: Dr Graham Lipkin, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. Email: graham.lipkin{at}uhb.nhs.uk



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Renal disease may present for the first time in pregnancy, either as symptomatic disease or as a consequence of antenatal screening. The role of antenatal and post-partum percutaneous renal biopsy in the management of such patients is discussed.

Methods. We describe two series of women; the first is a series of 20 women presenting with renal disease of a severity to warrant renal biopsy during pregnancy whilst the second, comprises 75 women who had an initial presentation of renal disease in pregnancy and underwent post-partum renal biopsy.

Results. Biopsy during pregnancy revealed a glomerular disorder in 19/20 (95%) with immediate change of management in 9/20 (40%). In 17/20 (85%) there was delivery of a live infant at median gestation of 36 weeks (range 25–40). Follow-up of women [median 103.3 months (2.5–256)] showed 9/20 (45%) had a GFR of <60 ml/min/1.73 m2 [six at end-stage renal failure (ESRF)] and 3/20 were dead. The majority (62/75; 82.6%) of women undergoing post-partum renal biopsy presented with significant proteinuria (40% pre-eclampsia) during pregnancy not resolving post-partum. A glomerular abnormality was found in 64%. At last follow-up of 47 women [median 51.5 months (range 1–212)], 14 patients (29.7%) had significant proteinuria and 20 (42.6%) had a GFR<60 ml/min/1.73 m2. Six women (12.7%) had ESRF.

Conclusions. Diagnosis and follow-up of renal disease diagnosed in pregnancy is important as progressive disease occurs in this group. Routine antenatal screening provides a useful diagnostic opportunity to detect asymptomatic renal disease. In a selected sub-group, renal biopsy during pregnancy can be helpful in initiation of correct treatment and allowing progression of pregnancy to fetal viability.

Keywords: chronic kidney disease; pre-eclampsia; pregnancy; proteinuria; renal biopsy



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Pregnancy in women with renal disease is associated with significant morbidity and increased mortality in both mother and fetus [2]. Moreover, in those with more advanced chronic kidney disease, there is a risk of pregnancy-induced progression of renal disease [1]. Renal disease may present for the first time in pregnancy as a consequence of screening. This may occur in the context of a known systemic disorder such as systemic lupus erythematosus, or as de-novo disease. In some situations, it may be important to know the exact aetiology of the renal disorder in order that immediate disease-modifying treatment can be commenced to enable the pregnancy to reach viability. However, in other circumstances, such as the detection of non-nephrotic range proteinuria in the absence of features of a systemic disease process, definitive diagnosis of renal disease can be delayed until post-partum. Renal biopsy has been performed during pregnancy since its introduction in the 1960s. Initial series showed a high incidence of complications [3] but subsequent reports indicate a complication rate similar to non-pregnant women [4,5]. Indeed one group recommend no modification of the indication for renal biopsy in pregnancy and suggest that all pregnant women with abnormalities in urinalysis indicative of renal disease should undergo renal biopsy to guide treatment [4], but this is not standard practice. Although it has been established that there is no greater risk of complications of renal biopsy in pregnancy, the consequences to the mother and fetus of post-biopsy haemorrhage could be severe.

We describe two series of patients; the first is a series of women who underwent renal biopsy during pregnancy and the second describes 75 women who were initially diagnosed for the first time with a renal disorder antenally but underwent renal biopsy post-partum. We report our experience with the safety of renal biopsy and long-term prognosis in these women. We suggest that only carefully selected women in whom results of renal biopsy are likely to guide immediate changes in therapy should undergo renal biopsy whilst pregnant. Those who present with disorders not requiring specific diagnosis-dependent intervention, or those who have reached a point in the pregnancy where fetal viability is high, should be considered for biopsy post-partum if no structural cause for renal dysfunction such as reflux nephropathy is identified. We also emphasize the importance of the ‘diagnostic window’ of antenatal screening for the identification of young women whose renal disease may otherwise go undetected.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Women were identified as having been biopsied either during pregnancy or post-partum as a result of conditions diagnosed during pregnancy from histo-pathological records or following referral from a combined renal–obstetric clinic in a university teaching hospital. Both medical and obstetric notes and computer records were then searched for histology and clinical reports.

Estimated GFR was calculated using the four-variable MDRD formula 186 x (Scr)–1.154 x (age)–0.203 x (0.742 if female) x (1.212 black) with serum creatinine in mg/dl [6]. This was not used to estimate renal function in pregnant women.

Chronic kidney disease categories are as NKF-KDOQI guidelines [7]. CKD 1, known renal disease with eGFR >90 ml/min/1.73 m2; CKD 2, eGFR 60–89 ml/min/1.73 m2; CKD 3, eGFR 30–59 ml/min/1.73 m2; CKD 4, eGFR 15–29 ml/min/1.73 m2; CKD 5, eGFR <15 ml/min/1.73 m2.

This study received both Local Research Ethics Committee and Trust Research and Development approval. Patient confidentiality was preserved with all data made anonymous.

As this series spanned 20 years, method of renal biopsy has changed; initial cases underwent biopsy using a 14G Trucut needle following prior ultra-sound localization of kidney. For the past 10 years, biopsies have been performed using real-time ultra-sound localization and auto-mated 16G or 18G disposable, spring-loaded biopsy needles. All renal biopsies were reported by a single consultant histo-pathologist according to standard methodology including immunoperoxidase assessment.

Pre-eclampsia was diagnosed by the association of clinical features such as rapidly rising serum urate and a falling platelet count or progressive transaminitis.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
Pregnancy
Twenty women underwent renal biopsy during pregnancy during 1983–2004. Median age at biopsy was 28 years (range 17–39) and median gestation at biopsy was 20.5 weeks (6–31.)

Indication for biopsy
Four patients had a previous diagnosis of lupus nephritis with a deterioration of renal parameters during pregnancy, four presented for the first time with proteinuria (measured as albuminuria) and positive autoimmune serology during pregnancy, four presented with first onset of nephrotic syndrome, three were biopsied in the first trimester with proteinuria and impaired renal function to assess degree of renal damage and five were biopsied in the second trimester with worsening proteinuria and hypertension.

All other parameters are summarized in Table 1.


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  		Table 1. Clinical features of women biopsied in pregnancy

 
Obstetric outcomes
Pre-eclampsia in this cohort was common and occurred in 7/20 (35%). Median gestation at delivery was 34 weeks (range 25–40 weeks) and nine of the women were delivered by Caesarian section. There were two intra-uterine deaths, one still-birth and one neonatal death (born at 25 weeks gestation).

Complications of biopsy
One patient had minor post-biopsy haematuria which settled spontaneously.

Nine of the 20 patients had an immediate change in therapy (mainly the initiation or increase in dose of immunosuppressive medication) as a consequence of knowledge of renal histology.

Follow-up of women who underwent renal biopsy in pregnancy
Median time of follow-up was 103.3 months (2.5–256). At last follow-up, nine (45%) had a GFR of <60 ml/min/1.73 m2 and of these six (30%) had reached end-stage renal failure (ESRF). Three (15%) of the women had died. Last recorded renal function and proteinuria is illustrated in Table 2. Of the 14 patients not reaching ESRF, 11 are on hypertensive medication with the remaining 3 having blood pressure measurements of less than 130/80 [2].


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  		Table 2. Results at follow-up [median 103.3 months (2.5–256)] for patients biopsied during pregnancy

 
Post-pregnancy biopsies
Seventy-five women underwent renal biopsy following pregnancy with abnormal renal parameters diagnosed either during pregnancy or immediately post-partum. Median age at biopsy was 31 years (15–55). Only those with acute renal failure were biopsied immediately post-partum. In those with persistent proteinuria (as measured by albuminuria) renal biopsy was generally delayed at least 6 months.

Indications for biopsy
Median creatinine at biopsy was 86 µmol/l (57–896) with a median estimated GFR (MDRD) of 70.5 ml/min/1.73 m2 (5–122). Ten women (13%) had an eGFR of >90 ml/min/1.73 m2, 37 (49%) an eGFR 60–89 ml/min/1.73 m2, 11 (15%) an eGFR of 30–59 ml/min/1.73 m2, 5 (7%) an eGFR of 15–29 ml/min/1.73 m2 and 4 women had an eGFR of <15 ml/min/1.73 m2. Data was missing on 8 (10% of women).

Fifteen women (20%) had albumin excretion of <0.3 g/24 h, 27 (36%) 0.3–2 g/24 h and 13 (17%) more than 2 g/24 h. Data was unavailable on 20 (26%).

Clinical presentation
Fifty (83%) of the women presented with proteinuria in pregnancy. In 23 cases this was associated with superimposed pre-eclampsia with proteinuria persisting for several months post-partum. Twenty-seven women presented with newly diagnosed proteinuria in the absence of pre-eclampsia. Six women presented with nephrotic syndrome, six with newly diagnosed renal impairment, four with isolated haematuria and three with acute renal failure.

Biopsy diagnosis
The majority (64%) of the women had a glomerular disorder (excluding thin glomerular basement membrane disease) on renal biopsy with focal segmental glomerulosclerosis (FSGS) being the most common histological disorder. Table 3 illustrates renal biopsy diagnoses in more detail.


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  		Table 3. Biopsy diagnosis of women diagnosed post-partum (n = 75)

 
Follow-up
Follow-up data is available on 47 patients with a median duration of 51.5 months (range 1–212). These are generally the patients with more severe disease at presentation, as those with minor abnormalities had been discharged to primary care follow-up. In total seven women had reached ESRF requiring renal replacement therapy. Degree of CKD and albuminuria are illustrated in Table 4.


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  		Table 4. CKD category and albumin excretion g/24 h at follow-up [median 51.5 months (1–212)] for patients undergoing renal biopsy post-partum

 
Outcome by category
Reassuringly those with thin glomerular basement membrane disease and normal renal biopsies by light microscopy have a good renal outcome at follow-up. The worst outcome occurs in those with interstitial non-glomerular disease with four of five being classified as CKD 3–5. Those reaching ESRF had diagnoses of renal transplant acute cortical necrosis following ante-partum haemorrhage and intra-uterine death, late tubulo-interstitial damage, late FSGS, renal tuberculosis, sickle cell nephropathy, glomerular dense deposit disease and lupus nephritis.

The diagnosis of pre-eclampsia made no difference to the CKD category at follow-up in those with proteinuria persisting following pregnancy with ~40% of both reaching CKD 3–5. (Figure 1).


Figure 1
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  		Fig. 1. Outcome by CKD category of patients following renal biopsy post-partum. Median follow-up 51.5 months (1–212 months).

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
Initial reports of renal biopsy in pregnancy described a high complication rate with Schewitz et al. [3] describing gross haematuria in 16.7% of 77 women, 4.4% developing peri-renal haematomas and one maternal death. However, a subsequent review of renal biopsies carried out during pregnancy found that in many cases these biopsies were carried out via the peritoneal route during Caesarean section and in women who were markedly hypertensive. In addition, this was prior to the recognition of the bleeding diatheses associated with pre-eclampsia [8]. In subsequent more recent series the complication rates are similar to those of non-pregnant subjects [4].

Whilst previous recommendations suggest performing renal biopsy only when there is as sudden deterioration of renal function before 32 weeks with no obvious cause or in the case of symptomatic nephrotic syndrome before 32 weeks, there remains a substantial variation in clinical practice.

Chen et al. [5] report a series of 15 pregnant women from Taiwan biopsied over 10 years between 1990 and 1999 with a median follow-up only of 2 years. Twelve had nephrotic syndrome, and the other three significant renal impairment. All underwent ultrasound guided biopsy between 20 and 25 weeks of gestation. Eight were diagnosed with lupus nephritis, three with chronic glomerulonephritis, two had mesangial proliferative GN, one endocapillary GN and one diabetic nephropathy. There was one stillbirth and five children were small for gestational age. After 2 years’ follow-up three of the women had died and another two reached ESRF.

We describe two series of women diagnosed with abnormal renal function during pregnancy or the immediate post-partum period. Twenty underwent renal biopsy during pregnancy and 75 following pregnancy. We describe prolonged follow-up in these groups and emphasize the progressive nature of renal disease in some of these patients The occurrence of ESRF in 6 of the 20 biopsied during pregnancy but only 6 of the 75 biopsied post-partum reflects the severity of the renal disease biopsied during pregnancy. Coincidentally with the severity of the renal disease there was a high incidence of obstetric complications in the women requiring a renal biopsy whilst pregnant.

In light of our experience we suggest that renal biopsy is not indicated in all pregnant women presenting with renal disease. We would recommend performing biopsies only in highly selected women before 28 weeks gestation in the presence of sterile urine and kidneys >10 cm in size where pre-biopsy coagulopathy or thrombocytopaenia has been excluded or reversed and blood pressure well controlled. The primary renal presentation should be such that knowledge of renal histology may be likely to lead to an immediate therapeutic intervention that would enable the pregnancy to progress to fetal viability.

In the first trimester we would consider performing a renal biopsy in those with structurally normal kidneys and an active urinary sediment, nephrotic syndrome, unexplained CKD (with proteinuria and no evidence of scarring) and those with evidence of renal impairment and proteinuria in the context of systemic disease or positive autoimmune serology. We feel a diagnosis at this stage of pregnancy is of benefit to guide treatment and allow an informed discussion of the risks:benefit ratio of continuation of pregnancy.

In the second trimester pre-eclampsia and any physiological rise in proteinuria should be first excluded. Renal biopsy should be reserved for those with unexplained nephrotic range proteinuria, progressive CKD and renal disease in the presence of active systemic disease. If these criteria are not met we would suggest performing a renal biopsy post-partum if indications remain. We would also suggest that after 28 weeks of pregnancy, when fetal viability is good, delivery should be induced if felt to be clinically necessary and biopsy performed post-partum.

We acknowledge that thin gauge needles and real-time ultrasound guidance ensure renal biopsies are safer than previously, but still use the procedure with caution as haemorrhagic complications will have severe consequences for the pregnancy.

It can be very difficult to distinguish between pre-eclampsia and primary renal disease and indeed often the two co-exist. However we would not recommend the routine use of biopsy to distinguish between the two diagnoses. The rate of complications following biopsy remains high in pregnant women with incomplete blood pressure control [9], and a biopsy made little difference to pregnancy outcome. Moreover, glomeruloendotheliosis may also be present in pregnant women without pre-eclampsia [10]. Differentiation is usually possible clinically by observing the rate of progression of proteinuria and hypertension, which is typically rapid in pre-eclampsia, and the association of other clinical features such as rapidly rising serum urate and a falling platelet count or progressive transaminitis. Measurements of the vascular endothelial growth factor receptor sFlt-1 which has been shown to be raised in women with pre-eclampsia compared to healthy pregnant women, and placental growth factor (PlGF), which is at lower levels, may in the future help to diagnose pre-eclampsia [11,12] although these parameters still need to be evaluated in patients with renal disease.

Routine urinalysis is performed throughout pregnancy to aid detection of glycosuria and pre-eclampsia and screen for asymptomatic bacturia. In addition, it enables the detection of previously undiagnosed renal disease. Those women presenting with proteinuria, either with or without pre-eclampsia, which persisted into the post-partum period, had significant renal disease with 19/40 having CKD 3–5 and six ESRF at last follow-up. In addition 14/34 women (without ESRF) had significant proteinuria of >0.3 g albuminuria/24 h. This reflects the results of a series reported by Stettler et al. [13] which demonstrated adverse pregnancy outcomes and long-term maternal mortality in women first diagnosed with proteinuria in pregnancy. Moreover, Nisell et al. [14] in a series of Swedish women showed that chronic hypertension 7 years after pregnancy-associated hypertension or pre-eclampsia was strongly associated with micro-albuminuria in pregnancy and thus residual renal disease. In our series, it is unlikely that the renal disease, which was often asymptomatic, would have been diagnosed without the pregnancy. We would therefore recommend that any women presenting with proteinuria before 20 weeks pregnancy, whether or not accompanied by subsequent superimposed pre-eclampsia, should be re-screened for proteinuria 6 months post-partum as by this point proteinuria associated with the renal lesion of pre-eclampsia has usually resolved. If the urine albumin:creatinine ratio remains abnormal the woman should be referred for further renal assessment. Antenatal screening for urine abnormalities presents an opportunity for diagnosis of significant renal disease in young women. It allows subsequent treatment of proteinuria, hypertension and cardiac risk factors in an attempt to both delay progression [15,16] of what may otherwise have been undiagnosed renal disease, and reduce the incidence of associated cardiovascular morbidity and mortality [17–19].



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Profesor Alec Howie for providing the list of biopsier performed in these women.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med (1996) 335:226.[Abstract/Free Full Text]
  2. Fischer MJ, Lehnerz SD, Hebert JR, Parikh CR. Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy. Am J Kidney Dis (2004) 43:415.[CrossRef][Web of Science][Medline]
  3. Schewitz L, Friedman I, Pollak V. Bleeding after renal biopsy in pregnancy. Obstet Gynecol (1965) 26:295.[Web of Science][Medline]
  4. Packham D, Fairley K. Renal biopsy: indications and complications in pregnancy. Br J Obstet Gynaecol (1987) 94:935.[Web of Science][Medline]
  5. Chen H-H, Lin H-C, Yeh J-C, Chen C-P. Renal biopsy in pregnancies complicated by undetermined renal disease. Acta Obstetricia et Gynecologica Scandinavica (2001) 80:888.[CrossRef][Web of Science][Medline]
  6. Levey A, Greene T, Kusek J, Beck G. A simplified equation to predict glomerular filtration rate from serum creatintine. J Am Soc Nephrol (2000) 200:155A.[CrossRef]
  7. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation Practice Guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med (2003) 139:137.[Abstract/Free Full Text]
  8. Lindheimer M, Davison J. Renal biopsy during pregnancy: 'to b ... or not to b ... ?' Br J Obstet Gynaecol (1987) 94:932.[Web of Science][Medline]
  9. Kuller JA, D'Andrea NM, McMahon MJ. Renal biopsy and pregnancy. Am J Obstet Gynecol (2001) 184:1093.[CrossRef][Web of Science][Medline]
  10. Strevens H, Wide-Swensson D, Hansen A, et al. Glomerular endotheliosis in normal pregnancy and pre-eclampsia. Br J Obstet Gynaecol (2003) 110:831.
  11. Williams WW Jr, Ecker JL, Thadhani RI, Rahemtullah A. Case 38-2005 — a 29-year-old pregnant woman with the nephrotic syndrome and hypertension. N Engl J Med (2005) 353:2590.[Free Full Text]
  12. Buhimschi CS, Magloire L, Funai E, et al. Fractional excretion of angiogenic factors in women with severe preeclampsia. Obstet Gynecol (2006) 107:1103.[CrossRef][Web of Science][Medline]
  13. Stettler R, Cunningham F. Natural history of chronic proteinuria complicating pregnancy. Am J Obstet Gynecol (1992) 167:1219.[Web of Science][Medline]
  14. Nisell H, Lintu H, Lunnell N, Mollerstrom G, Pettersson E. Blood pressure and renal function seven years after pregnancy complicated by hypertension. Br J Obstet Gynaecol (1995) 102:876.[Web of Science][Medline]
  15. Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in Type 2 diabetes and nephropathy. N Engl J Med (2004) 351:1952.[Abstract/Free Full Text]
  16. Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in Type 2 diabetes. N Engl J Med (2004) 351:1941.[Abstract/Free Full Text]
  17. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C-y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med (2004) 351:1296.[Abstract/Free Full Text]
  18. Arnlov J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation (2005) 112:969.[Abstract/Free Full Text]
  19. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation (2004) 110:32.[Abstract/Free Full Text]
Received for publication: 11. 2.07
Accepted in revised form: 26. 7.07


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