Chronic kidney disease (CKD) is increasingly encountered in pregnancy because of greater diagnostic awareness, which is a reflection of the newer, broader definitions (i.e., any changes in blood or urine composition or at imaging, or a glomerular filtration rate (GFR) of <60 mL/min lasting at least 3 months) and of increased incidence (higher maternal age and better outcomes of several kidney diseases).
CKD is extremely heterogeneous and may be described by the degree of GFR reduction (CKD stages), the presence of proteinuria and hypertension and the type of kidney disease; the risk of adverse pregnancy-related events increases as GFR decreases and it is affected by proteinuria and hypertension. Specific risks are reported in various diseases such as lupus nephropathy or diabetic nephropathy. While transplantation at least partially restores fertility in end-stage kidney disease, pregnancy on dialysis is increasingly reported.
This chapter deals with the available evidence on the management of CKD patients in pregnancy.
Highlights
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Chronic kidney disease (CKD) is a challenge in all stages.
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The risk of adverse events increases as kidney function worsens.
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The risk is higher in the presence of proteinuria and hypertension.
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Strict multidisciplinary follow-up is needed.
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Success may be achieved in all stages, including on dialysis.
Introduction
Chronic kidney disease: a matter of definition
Almost 20 years ago, the National Kidney Foundation started a campaign entitled ‘The Fight against the Silent Killers’ . These silent killers were chronic kidney diseases (CKD), and they were defined as ‘silent’ because they were frequently asymptomatic until renal failure occurred, and they were ‘killers’ as kidney disease affects survival . Presently, after acknowledging the risks in elderly patients, the definition of ‘silent killer’ may be applied to CKD in pregnancy, as these often undiagnosed diseases are a main cause of morbidity in pregnancy .
CKD is currently broadly defined as any alteration in renal morphology, imaging or function, or by a glomerular filtration rate (GFR) <60 mL/min for at least 3 months . Despite the revisions and criticisms, the advantage of this definition is that it focuses on the earlier CKD stages, when kidney function is still normal and the potential for recovery is higher .
Serum creatinine, which is derived from muscle mass, is physiologically lower in women and in small body size; furthermore, in pregnancy physiological hyperfiltration may mask an initial GFR reduction, thus leading to underestimation of CKD in pregnancy . Changes in GFR are not an ‘early’ marker of disease, as it starts decreasing when >50% of the renal parenchyma is damaged; hence, it is important to identify CKD in stage 1, when kidney function is normal and CKD is revealed by proteinuria, haematuria, electrolyte derangements, tubulo-interstitial diseases, single kidney (including kidney donation) or even ‘simple’ kidney scars due to previous acute pyelonephritis .
On the basis of these broad definitions, the prevalence of CKD reaches 3% in women in childbearing age, a significant difference as compared to previous definitions, which were based upon high creatinine levels that probably identified <10% of cases .
Pregnancy is a very important opportunity to diagnose kidney disease in an apparently healthy woman. In our experience, CKD is diagnosed or acknowledged as a risk factor in pregnancy in at least 40% of cases . The physiological increase in GFR, the lack of validated formulae for GFR assessment in pregnancy and the clinical and laboratory overlap with pre-eclampsia (PE) are important challenges for early diagnosis as discussed below . We also discuss how CKD bears a risk of adverse pregnancy-related outcomes starting from the early stages, and even ‘minor’ signs of CKD should be taken into consideration .
In the following paragraphs, we summarise the available evidence and its limits, sharing our points of view on the diagnosis and care of CKD in pregnancy.
What is ‘inside CKD’?
Regardless of how it is defined, CKD is a syndrome and not a disease; its main descriptors are kidney function, kidney disease, proteinuria and hypertension ( Fig. 1 ).
Kidney function, which is subdivided by the Kidney Disease Outcomes Quality Initiative (K-DOQI) definition into five stages, is probably the most powerful descriptor of the severity of the disease and of the risk of complications .
As a rule, immunologic and systemic diseases (such as glomerulonephritis, or diabetic or lupus nephropathies) are more frequently associated with adverse pregnancy-related events; conversely, interstitial kidney diseases share a higher risk of upper urinary tract infection (UTI), unexplained oedema or stone disease .
Hypertension and proteinuria are independently correlated with CKD progression and with adverse pregnancy-related events, and, when present, PE may be difficult or impossible to diagnose .
What is ‘inside CKD’?
Regardless of how it is defined, CKD is a syndrome and not a disease; its main descriptors are kidney function, kidney disease, proteinuria and hypertension ( Fig. 1 ).
Kidney function, which is subdivided by the Kidney Disease Outcomes Quality Initiative (K-DOQI) definition into five stages, is probably the most powerful descriptor of the severity of the disease and of the risk of complications .
As a rule, immunologic and systemic diseases (such as glomerulonephritis, or diabetic or lupus nephropathies) are more frequently associated with adverse pregnancy-related events; conversely, interstitial kidney diseases share a higher risk of upper urinary tract infection (UTI), unexplained oedema or stone disease .
Hypertension and proteinuria are independently correlated with CKD progression and with adverse pregnancy-related events, and, when present, PE may be difficult or impossible to diagnose .
Limits of the currently reported evidence
Despite the increased interest, evidence regarding CKD in pregnancy is scant and heterogeneous. There are several reasons for this, including fragmented literature that lacks a common language, the involvement of various diseases, the fact that it is subject to referral biases and that it is influenced by the study setting .
There are at least four reasons for these limitations. Firstly, the changes in definitions that have only recently been integrated into obstetric nephrology make pooling of data difficult. Secondly, CKD is heterogeneous as it is made up of several ‘families’ of diseases. Thirdly, progression of CKD differs from patient to patient, and the role of disease modulators (including proteinuria, hypertension, nutritional status and lifestyle) is still unknown. Fourthly, the lack of ‘low-risk pregnancy’ control groups in many studies hinders contextualization of the results as the baseline risks vary widely around the world, and they depend on genetic background, lifestyle and health-care systems.
Risks for the mother and child
There are three main risks for CKD mothers: worsening of kidney function, development of the hypertensive disorders of pregnancy with possible persistence of hypertension after delivery and death .
There are four main risks for the child: prematurity (with all its sequelae), inheritance of maternal diseases, malformations and side effects of maternal therapies .
Main risks for the child
The main risks for the foetus are linked to prematurity. A detailed discussion is beyond the scope of this review; however, it must be mentioned that an increase in CKD in adulthood has been reported in ‘small’ babies, even if this term was often employed ambiguously, overlapping small, small-for gestational-age (SGA) and intrauterine growth-restricted babies .
Children of CKD mothers are not reported as being at a higher risk of malformations . The only exception is one study that reported a higher incidence of malformations in children of mothers with nephropathy and diabetes as compared to diabetes alone .
The genetics of kidney diseases is only partially known. Besides the most common Mendelian diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome (heterogeneous, usually X-linked), many genes have not been identified: this is the case with immunoglobulin A (IgA) nephropathy, probably the most common form of glomerulonephritis in young adults, with 30% positive family history . Inheritance is often multifactorial, as in vesico-ureteral reflux, while other malformations of the urinary tract are linked to various genes . Hence, the possibility that kidney diseases recur in the offspring cannot be excluded and should probably be mentioned in counselling .
Commonly used drugs in CKD and potential effects on the foetus
CKD therapy is often complex and multiple drugs are routinely needed in advanced CKD, systemic diseases and kidney transplantation. Tables 1 and 2 summarise some information on the most commonly used drugs in CKD, that is, antihypertensive and immunosuppressive drugs with particular regard to CKD patients .
| Drug | Main features | FDA | SOGC |
|---|---|---|---|
| Usually considered first-choice drugs | |||
| Alpha-methyldopa | Widely used in pregnancy, with no reported negative effects on the foetus or on its subsequent development. May not be able to correct severe hypertension in CKD. | B | 1-A |
| Nifedipine | The long-acting drug is most commonly used in hypertension in pregnancy. The increase in peripheral oedema may be a relevant side effect in CKD patients. | C | 1-A |
| Labetalol | Usually well tolerated, should be avoided in subjects with asthma. In an RCT, it was shown to be comparable to alpha-methyldopa | C | 1-A |
| Usually considered second-choice drugs | |||
| Beta blockers | The main drawback in older studies was foetal growth restriction, possibly as an effect of overzealous correction . Beta1-selective beta blockers (atenolol) are more often involved. Beta blockers may be more effective than alpha-methyldopa in severe hypertension, alone or in combined therapy. At delivery, they may induce hypoglycaemia, hypotension and bradycardia (usually mild and transient) | D atenolol B pindolole C metoprolol. | 1-B |
| Clonidine | The effect is similar to alpha-methyldopa; side effects may be more common and hypertensive rebounds at discontinuation are common; slowing foetal growth is occasionally reported | C | |
| Diuretics | They are usually avoided in pregnancy except for nephrological or cardiological indications. Thiazides may be continued in patients previously on treatment . In selected cases with Gitelman syndrome, amiloride may be employed . | B hydrochlorothiazide amiloride | |
| To be avoided | |||
| Short-acting nifedipine | Contraindicated by the FDA, RCOG and AIPE due to the risk of severe sudden hypotension with detrimental effects on placental flows | D | |
| ACE-i ARB and related drugs | Both drugs are contraindicated in all phases of pregnancy because of the risk of several major malformations, including cardiovascular, central nervous system, renal and bone malformations . See text on pre-emptive discontinuation. | C 1st D 2nd – 3rd trimester | II 2E |
| Drug | Main features | FDA |
|---|---|---|
| Usually considered as relatively safe, when absolutely needed | ||
| Azathioprine | This is the most widely used immunosuppressive drug. It is teratogenic in animal models, but not in humans, possibly because the foetal liver is not able to activate the drug. K-DIGO and European Best Practice Guidelines suggest switching from mycophenolate to azathioprine before pregnancy | D |
| Cyclosporine A | This calcineurin inhibitor has not been associated with increased teratogenicity; however, small-for-gestational-age babies and preterm delivery have been reported, possibly due to the maternal disease and not specifically to the drug; levels may vary in pregnancy and the hypertensive, hyperglycaemic and nephrotoxic effects should be mentioned | C |
| Tacrolimus | The drug has similar effects and side effects to Cyclosporine A; as it is a relatively new drug, experience is more limited than with the previous drug | C |
| Steroids | Together with azathioprine, these are the most often employed and best-known drugs. The most frequently used short-acting corticosteroids include prednisone, methylprednisolone and prednisolone, while betamethasone and dexamethasone are among the long-acting drugs. No major malformations have been reported, and the issue of labio-palatoschisis is debated. A higher risk of premature rupture of membranes has been reported. Other relevant side effects include infectious risk and the increased risk of gestational diabetes | C |
| Hydroxychloroquine | This synthetic antimalarial agent crosses the placenta but was not found to be associated with foetal toxicity | N |
| To be avoided | ||
| Cyclophosphamide | This alkylating agent is contraindicated in pregnancy; a few reports suggest that pregnancy termination is common in the case of inadvertent use or need for life-saving therapy. A few positive reports, mainly in women with SLE are also available | D |
| Methotrexate | This teratogenic agent is also employed for extrauterine pregnancy termination. Discontinuation for one to three menstrual cycles is usually indicated | X |
| Mycophenolate | Severe foetal malformations are reported, mainly involving cardiovascular and cranial malformations. Discontinuation for at least 6 weeks, to stabilize kidney function, is usually indicted after kidney transplantation | D |
| m-Tor inhibitors | Very few studies considered their use in pregnancy. They are teratogenic in animals and discontinuation in humans is a matter of debate; KDIGO guidelines suggest discontinuation in anticipation of pregnancy | C |
While the advantages of universal treatment for mild to moderate hypertension are controversial in the general population, nephrologists usually prefer normal or low–normal blood pressure targets. However, to the best of our knowledge, no randomised trials have ever been performed involving hypertensive CKD patients in pregnancy, thus leaving each group free to individually define the choice of the treatment policy .
An important point regards the discontinuation of potentially dangerous drugs. Contrary to the guidelines on hypertension and pregnancy, many nephrologists, including our group, prefer to discontinue angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor inhibitors on the occasion of a positive pregnancy test, at least in compliant, reliable patients, with a regular menstrual cycle agreeing to perform the test immediately after missing menstruation. This is motivated by the absence of a ‘carry-over effect’ (meaning that once stopped, they do not have any lingering teratogenic effect) and by the fact that, in particular in patients with proteinuric diseases, this policy allows us to maximize nephroprotection and to start a pregnancy with minimal proteinuria ( Table 1 ).
On the contrary, preventive discontinuation and/or switch to a different type of drugs may be indicated for several immunosuppressors, because of the risk of flare-ups of immunologic diseases, such as systemic lupus erythematosus (SLE) or of rejection after kidney transplantation if the changes are performed during pregnancy ( Table 2 ).
Pregnancy in the various CKD stages
Renal function impairment is a major determinant not only of pregnancy outcomes but also of fertility, which is progressively lost across CKD stages and only partially restored after transplantation . As mentioned, the risk of adverse pregnancy-related events increases with renal function impairment . Quantifying the risk is difficult due to the heterogeneity of the studies. In a recent meta-analysis, a combined outcome was analysed (merging the risks of gestational hypertension, PE, eclampsia and maternal mortality), and the risk was found to range from 2 to >10 times that of the control population . Fig. 2 reports the risk pattern across stages obtained in a large series of CKD patients observed in two Italian settings (the ToCOS cohort, Torino Cagliari Observational Study).
Special considerations: stages 1–2
Renal function is normal in stage 1 CKD (GFR >90 mL/min) and in the ‘grey area’ of mildly reduced kidney function in stage 2 (90–60 mL/min), with persistent signs of disease, including proteinuria, haematuria, kidney scars, electrolyte disorders or kidney stones. Interestingly, a baseline risk of adverse pregnancy outcomes persists also in subjects without hypertension, proteinuria or systemic diseases: in three large series of kidney donors, the risk of adverse pregnancy-related events, mainly PE, was about twice as high after donation than before, even if the odds of PE remained low due to careful donor selection . A study on a Saudi Arabian population showed that even in these early stages of CKD, the risk of prematurity as well as the need for neonatal intensive care unit (NICU) and caesarean sections increased by two- to sixfold from CKD stage 1 to stage 2 . Progression of kidney disease is rare in these disease stages, as suggested by a large series of IgA nephropathy and early diabetic nephropathy; analogous data were found in our stage 1–2 CKD patients .
Therapeutic approaches : Therapeutic interventions are mainly linked to the baseline disease, proteinuria and hypertension (see the following paragraphs). In their absence, the only ‘therapeutic tool’ is close clinical surveillance, with attention to the signs heralding hypertensive disorders of pregnancy .
Counselling hints : There is still little evidence on the outcome of early CKD in pregnancy. In most series, preterm delivery is two- to fourfold higher (in our experience mainly late preterm); the odds of needing NICU or of having a small baby are consequently increased. The reasons for this increase, in the absence of hypertension and proteinuria, are not known. Hence, counselling should underline the uncertainties and the need for close surveillance of all pregnancies in CKD patients .
Special considerations: stage 3
CKD stage 3 is defined by a GFR of 60–30 mL/min. This implies a decrease in kidney parenchyma ranging from 15% to 30%, following the ‘rule of thumb’ that the amount of renal tissue is about half of the renal function. While in elderly patients this may be the result of vascular ageing, in young patients it is mainly the result of progressive disease; consequently, the prevalence of glomerular and systemic diseases is higher in this subset .
Therapeutic approaches : Besides treatment for the underlying disease and, when needed, the metabolic correction described for CKD stages 4–5, in our experience a moderate decrease in dietary protein intake with vegan–vegetarian diets may be of help, most likely by counterbalancing the effects of hyperfiltration on the remnant nephrons . Strict clinical surveillance is recommended ( Table 3 ).
| Disease or condition | Minimal follow-up | Main biochemical tests prescribed | Imaging | Other |
|---|---|---|---|---|
| Stage 1 CKD [not otherwise specified (nos)] | 4–6 weeks | Every 4–6 weeks: urinalysis, urinary culture, Na, K, Ca, P, albumin, creatinine, urea, uric acid; clearance and proteinuria on 24-h urine collection every 10–12 weeks; | Renal ultrasounds if not performed in the previous year | Nutritional parameters at start: ferritin, vit D, B12, folates, albumin, total proteins |
| Stage 2 CKD (nos) | 4 weeks | Like stage 1, frequency increased to 4 weeks | Same as above | Like stage 1, every 10–12 weeks |
| Stage 3 CKD (nos) | 3 weeks | Same as above; monthly 24-h urine collection | Same as above | Same as above; monthly in on-diet patients |
| Stages 4–5 CKD (nos) | 1–2 weeks | Same as above; 24-h urine collection twice monthly | Same as above | Same as above; monthly in on-diet patients |
| Hypertension | According to stage; at least weekly in the case of non-controlled BP | According to stage. | Echocardiography if not performed in the previous year | Home BP profile; 24-h BP monitoring in the case of doubts |
| Glomerulonephritis in remission (CKD stage 1, proteinuria <0.3 g/day) | According to stage; at least monthly in SLE | Urinalysis every 1–2 weeks, checking for proteinuria | Same as above | Other tests according to the type of glomerulonephritis (i.e., autoantibodies in SLE); immunological profile at start and end of pregnancy. |
| Proteinuria >0.3 to <3 g/day | According to stage; minimum 4 weeks | 24-h proteinuria, clearances and serum albumin at least monthly; IgG, IgA and IgM; coagulation with antithrombin III every 10–12 weeks | Same as above | Same as above (glomerulonephritis) |
| Proteinuria>3 g/day | According to stage; minimum 2 weeks | Same as above; proteinuria at least twice monthly | Same as above | Same as above |
| Previous acute pyelonephritis and diseases at risk of UTI including malformations and ADPKD | According to stage; if no infection every 4–6 weeks | According to stage plus urinalysis and urinary cultures every 1–2 weeks; calciuria in the case of kidney stones | Renal ultrasounds every 10–12 weeks, increased frequency in the case of dilatation or colic | – |
Counselling hints : The reported risk of kidney function worsening varies in the literature (20–50% of cases) . The prevalence of prematurity increases as kidney function worsens, becoming almost the rule in stages CKD 4–5 (in our experience >75% of children of CKD stage 3 mothers are born preterm and about half are delivered before the 34th gestational week). This is closely connected to the need for NICU that occurred in >40% of the babies in our series ( Fig. 2 ). To our knowledge, there are currently no studies examining the psychological impact of this need for ‘special care’ in CKD mothers.
Special considerations: stages 4 and 5 (not on renal replacement therapy)
Kidney function is severely reduced (stage 4: GFR 30–15 mL/min, stage 5: GFR <15 mL/min), and hypertension and proteinuria are increasingly encountered in CKD stage 4 and 5 patients. Although the recent guidelines on the start of dialysis have shifted towards lower GFR, some centres prefer to start renal replacement therapy early in younger patients . Where available, patients in CKD stages 4–5 are frequently wait-listed for pre-emptive transplantation.
Therapeutic approaches : Strict clinical surveillance is fundamental. The importance of the baseline disease may decrease when CKD progresses as the ‘end stage’ involves all of the kidney structures. Therapy is aimed at correcting the four main metabolic derangements: malnutrition, anaemia, calcium–phosphate parathyroid hormone (PTH) balance and acidosis. Malnutrition is frequently reported as an effect of both the hyper-catabolic effect of advanced CKD and the decreased appetite induced by acidosis and correlated with urea levels. Malnutrition is a constant threat in advanced CKD, and attention should be paid to reaching the caloric target of 30–35 kcal/kg/day to reduce protein wasting.
The diet issue is, however, discussed. In our experience, vegan–vegetarian diets may be used for counterbalancing the hyperfiltration of pregnancy, in particular in patients with advanced CKD or proteinuria, in whom ACE inhibitors and angiotensin receptors inhibitors have to be discontinued. At least in our single-centre pioneer experience, vegan diets, with a protein intake of 0.7–0.8 g of proteins kilograms of body weight, strictly controlled for the risk of malnutrition, were safe in pregnancy and were associated with a lower incidence of SGA babies and possibly with a stabilizing effect on kidney function and proteinuria . However, these promising data need confirmation on a larger scale. Anaemia, due to erythropoietin deficit, is a common threat, and it is associated with impaired intrauterine growth. Erythropoietin does not cross the placenta, and it is considered safe in pregnancy.
The need for erythropoietin usually increases in pregnancy and the optimal response is attained at ferritin levels of 200–400 ng/mL, thus enhancing the need for iron supplementation . CKD patients are also at a risk of B12 deficiency, in particular when on protein-restricted diets. The calcium–phosphate balance is frequently impaired due to the lack of hydroxylation of 25-OH vitamin D in the kidney. Recently, attention has been drawn to the importance of 25-OH vitamin D . Low vitamin D levels have been (albeit non-consistently) associated with an increased risk of PE and other pregnancy-related adverse events. As baseline levels are often already low in CKD patients, we suggest correcting at least the main deficiencies.
The lack of regeneration of bicarbonates in the failing kidney is the basis of acidosis, another progression factor for CKD . Acidosis may cause hyperkalaemia, a potential threat in advanced CKD. Bicarbonate therapy has no contraindications in pregnancy; oral bicarbonate is preferable as intravenous (i.v.) bicarbonate is associated with an acute water and sodium overload.
Counselling hints : Reports on both the risk of GFR worsening and the need for dialysis during or immediately after pregnancy differ, but they may be estimated as occurring in 50–75% of cases . Our results show a lower incidence (22% CKD 4–5 shifted by one CKD stage or started dialysis), but they are based on a small number of cases ( Fig. 2 ). Proteinuria and hypertension may either appear or worsen during pregnancy in up to 70–80% of cases.
Foetal risks : The prematurity risk is high, being almost the rule in most series . The need for drug therapy may expose the foetus to iatrogenic consequences ( Tables 1–2 ).
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