15th July 2024

Renal physiology and dysfunction in pregnancy

Renal physiology

During pregnancy, there is a physiological increase in glomerular filtration rate (GFR), secondary to an increase of approximately 60% in renal blood flow due to increased cardiac output and blood volume. As a result, in pregnant women with normal renal function, creatinine decreases in the first trimester. This can occur as early as the 5th week of pregnancy. During the last few weeks of pregnancy, GFR falls, and therefore creatinine increases, so that renal function returns to baseline shortly postpartum, although GFR can be reduced for up to the first 3 months postpartum. A creatinine above 75µmol/l (0.87mg/dl) should be considered abnormal in pregnancy, indicating renal impairment either secondary to pre-existing renal disease or acute kidney injury. In pregnancy, estimated GFR (eGFR) is not a reliable marker of kidney function.

The increase in GFR in pregnancy can lead to glycosuria in 50% of pregnant women, even with a normal blood sugar, as the kidney tubules are unable to reabsorb all glucose from the filtrate back into the blood. Similarly, mild proteinuria (up to 300 mg over 24 hours) can also occur in pregnancy due to the same mechanism. However, a urine protein creatinine ratio (uPCR) above 30 mg/mmol or a urine albumin creatinine ratio (uACR) above 8 mg/mmol warrants urgent referral to obstetrics.

Other changes during pregnancy occur in the anatomy of the urinary tract itself. The smooth muscle of the renal pelvis relaxes, leading to dilation and a physiological hydronephrosis that requires no intervention or treatment.

Chronic kidney disease

Currently, chronic kidney disease (CKD) affects 3% of pregnancies, and it is likely its incidence will increase. All stages of CKD lead to an increased risk of adverse outcomes, including miscarriage, intrauterine growth restriction and preterm labour. CKD is also a risk factor for pre-eclampsia, the risk and severity of which increases with worsening CKD. For women with progressive CKD, pregnancy accelerates the deterioration of their renal function. Therefore, antenatal counselling and close monitoring during pregnancy is critical. Prior to conception, poorer baseline renal function is associated with lower fertility rates due to lower oestrogen/progesterone, decreased FSH and LH, earlier menopause and often reduced sexual interest.

Women with pre-existing nephrotic range proteinuria (uPCR>300 mg/mmol or uACR>250 mg/mmol) should take low molecular weight heparin when pregnant. This is usually continued until 6 weeks postpartum.

Target blood pressure for women with CKD in pregnancy is below 135/85 mmHg.

Diagnosis and Management

In pregnancy, the following medications can safely continue:

• Tacrolimus
• Hydroxychloroquine
• Azathioprine
• Metformin
• Antihypertensives: Labetalol, Nifedipine, Methyldopa
• Erythropoietin analogues, e.g. Neorecormon and Aranesp (requirement increases in pregnancy)
• Activated vitamin D e.g. Alfacalcidol
• Steroids

Women taking calcineurin inhibitors or steroids during pregnancy should be screened for gestational diabetes.

Prior to pregnancy, administration of the following medications should be discontinued:

• Cyclophosphamide – stop 3 months prior to conception
• Methotrexate – stop six months prior to pregnancy
• Mycophenolate mofetil – stop 3 months prior to conception
• Rituximab – advise to avoid conception for 1 year after treatment (guidance may change)
• ACE inhibitors – can continue until conception
• Angiotensin receptor blockers – should discontinue prior to pregnancy
• Avoid sirolimus/everolimus
• Non-calcium-based phosphate binders
• Cinacalcet
• Diuretics should not be used to treat hypertension in pregnancy but can be used for symptomatic fluid overload

Contraception after cessation of medication before the safe time for conception; this time is known as the “washout period”. For women with CKD, oestrogen-containing contraceptives are usually contraindicated as they lead to increased risks of hypertension, as well as thromboembolism (especially for women with antiphospholipid syndrome or the nephrotic syndrome) and cervical malignancy (especially for women on immunosuppression). Progesterone based systems e.g. the Mirena coil and progesterone-only pill are acceptable. The copper intrauterine device can also be used.

If breastfeeding, the following medications can still be administered:

• Steroids
• Azathioprine
• Hydroxychloroquine
• Tacrolimus
• Everolimus

Renal conditions, such as glomerulonephritides, can present de novo in pregnancy. These can present very similarly to pre-eclampsia, with new proteinuria and renal impairment. However, pre-eclampsia does not lead to haematuria or the presence of red cell casts in the urine. Renal biopsy can be performed antenatally, although between 23-28/40 weeks, there is the highest risk of complications. After 28 weeks, most common presentations are haematomas and loin pain post procedure. A new presentation of nephrotic syndrome or acute glomerulonephritis may warrant a renal biopsy, although this must be balanced against the risks of biopsy and whether it will change treatment.

Increasingly, it is recognised that despite impaired fertility, women with end stage renal disease (ESRD) can become pregnant, although the rate of perinatal death is 50% for women established on dialysis, and 25% for those who start dialysis while pregnant. Women aiming to conceive should change from peritoneal dialysis (PD) to haemodialysis (HD) during pregnancy, as this reduces the risk of prematurity.

For women with progressive renal dysfunction, dialysis, i.e. haemodialysis, should be initiated with a urea level of 17 mmol/L or above, as urea is foeto-toxic. A target urea below 12 mmol/L should be aimed for. This usually requires more intensive dialysis. For anuric women on dialysis (i.e. those with no residual renal function), the target should be 36 hours of dialysis a week (usual dialysis regimens are 9-12 hours). This intense dialysis can lead to hypophosphataemia in the mother, which increases the risk of cervical shortening, and therefore, this must be replaced on dialysis.

Women with renal transplants should wait 1-year post transplant before conceiving. Women with SLE should be at least 6 months into remission on stable treatment before conceiving.

References

• Harel Z, McArthur E, Hladunewich M, Dirk JS, Wald R, Garg AX, Ray JG. Serum Creatinine Levels Before, During, and After Pregnancy. JAMA. 2019 Jan 15;321(2):205-207. doi: 10.1001/jama.2018.17948. PMID: 30644975; PMCID: PMC6439761
• Wiles K, Chappell L, Clark K, Elman L, Hall M, Lightstone L, Mohamed G, Mukherjee D, Nelson-Piercy C, Webster P, Whybrow R, Bramham K. Clinical practice guideline on pregnancy and renal disease. BMC Nephrol. 2019 Oct 31;20(1):401. doi: 10.1186/s12882-019-1560-2. PMID: 31672135; PMCID: PMC6822421
• National Institute for Health Care Excellence. Urinary tract infection (lower): antimicrobial prescribing London: NICE; 2018.(NICE Guideline No. 109). Available from: https://www.nice.org.uk/guidance/ng109/chapter/recommendations
• Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Gülmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014 Jun;2(6):e323-33. doi: 10.1016/S2214-109X(14)70227-X. Epub 2014 May 5. PMID: 25103301