EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Introduction
About 10% of the global adult population has chronic kidney disease (CKD), which is among the 20 leading causes of death1; CKD has detrimental consequences for both patients and their families. Of particular importance is women’s health and “kidney health” for the current population and for future generations. We are presented not only with a unique opportunity to learn as much as possible about the characteristics of kidney disease in women but also to use the knowledge gained more widely. Women make a huge contribution to society, not to mention their essential role in family life, not only in having children, giving birth, and feeding and raising children but also in caring for the health of the family and society as a whole. Here, we have provided examples from our own practice and answered a number of questions regarding pregnancy in women after kidney transplant.

Cohort studies have shown that the prevalence of CKD in women is always lower and the rate of progression toward end-stage renal disease (ESRD) is lower than in men.^2-4 However, we do not know whether this is due to differences in the detection of kidney lesions, differences in access to medical care, or true differences in the severity of the process and morbidity (and if so, to what extent). The risk of developing cardiovascular disease in women with CKD is higher than in women without CKD5 but still lower than in men with the same degree of kidney damage. In hemodialysis, there are differences in the types of vascular access between women and men, which may be associated with biological and systemic factors. In some regions, there are differences in the use of peritoneal dialysis and hemodialysis in women and men. We know that women are more likely to donate a kidney for a transplant than they are to receive one. However, we do not know if this is because of differences in the incidence of CKD in women compared with men or because of sociocultural factors or other reasons. We know that disparities in access to health care for women persist in many regions of the world, but we do not have data to measure these disparities directly, especially in the poorest countries and regions.

The most effective treatment for patients with CKD is kidney transplant. A successful operation is the best way to restore a patient’s quality of life. It is generally accepted that transplant technologies are highly effective modern methods for the rehabilitation of patients with irreversible chronic diseases of these vital organs.⁶ Many recipients of solid-organ transplant (both kidneys and livers) are women of reproductive age, and the restoration of fertility is an important step in medical and social rehabilitation.⁷ Modern advances in medicine have shown the possibility of pregnancy and the birth of a healthy child in this category of patients.^7-9

Patients with ESRD have reduced reproductive ability. Data from Europe and Australia indicated that there is a 1:10 ratio between female kidney transplant recipients and the general population, which is the same ratio between women on hemodialysis and female kidney transplant recipients (women on hemodialysis have a 1:100 chance of getting pregnant versus the general population).^10,11 The first cases of successful pregnancy of women on hemodialysis were described in the 1970s; today, the possibility of pregnancy in women on hemodialysis has become generally recognized.^12-14

Pregnancy places a particular strain on a woman’s body and is the leading cause of acute kidney injury in women of childbearing age. Both acute kidney injury and preeclampsia can lead to the subsequent development of CKD; however, the extent of the actual risk is not entirely clear.^15-18 In turn, CKD, even in the early stages, has a negative effect on the course of pregnancy.^19,20 The risk of an increased rate of progression of CKD poses serious ethical issues regarding the onset and prolongation of pregnancy.^19,20 We know that preeclampsia increases the likelihood of developing arterial hypertension and CKD in the long term.^21-24 We also know that systemic diseases such as systemic lupus erythematosus, rheumatoid arthritis, and systemic scleroderma are more common in women than in men. However, we do not know what the contribution of these conditions is to the progression to ESRD in women.

If systematic clinical and laboratory monitoring of renal parameters is carried out at least once every 2 weeks in the first and second trimester of pregnancy and weekly in the third trimester of pregnancy, a favorable course of pregnancy can be achieved. Changes in indicators during pregnancy may occur due to transient impairment of kidney function, usually in the third trimester due to transplant rejection and/or with the development of pregnancy complications (in particular, preeclampsia). The course of pregnancy is determined by the nature and severity of its complications, which is invariably manifested by the negative dynamics of these clinical and laboratory parameters.

Reproductive ability is partly restored after kidney transplant.^25-28 However, even in an ideal situation (normal graft function, absence of hypertension and proteinuria, and absence of rejection episodes for at least 2 years posttransplant), the risk of complications in female transplant recipients is higher than in the general population. In general, if the use of teratogenic drugs (mycophenolic acid and rapamycin) is excluded, pregnancy outcomes after kidney transplant are associated with the same risk factors as in CKD in general (renal function, hypertension, and proteinuria). Studies on pregnancy management in women with reduced or almost completely lost graft function are limited, and counseling in such cases is based mainly on the individual experiences of the doctor and on indirect evidence.^29-33

Our own experiences in the management of pregnancy in women with transplanted organs and data from literature suggest that a successful pregnancy is possible with stable graft function. Careful monitoring of the function of the graft, the pregnant recipient of the kidney, and the fetus throughout the entire period of gestation is an indispensable requirement for a successful outcome.

According to our experiences, one of the most important criteria for prolonging pregnancy in women with solid-organ transplants should be the consideration of pregnancy at least 1 year after transplant. As a rule, by this time, a stable level of maintenance immunosuppression is achieved, ensuring the absence or low severity of dysfunction of other organs and a minimal risk of infectious diseases. Serum creatinine level up to 150 µmol/L, urea up to 12 mmol/L, proteinuria up to 0.5 g/day, glomerular filtration rate (GFR) of 40 mL/minute are defining markers of normal (or moderately elevated but stable) levels of hepatic cytolytic enzymes (alanine aminotransferase and aspartate aminotransferase); normal levels of platelets, bilirubin, albumin, protein C, antithrombin III, and prothrombin index can show satisfactory functions of the liver graft. A serious criterion to show the stable function of any transplant is the absence of arterial hypertension or a controlled adequate level of arterial blood pressure of up to 140/90 mm Hg. According to various studies, hypertensive disorders are associated with a high incidence of adverse pregnancy outcomes in recipients of solid-organ transplant. Our experiences have shown that clinical and laboratory monitoring of significant laboratory parameters should be conducted at least once every 2 weeks in the first and second trimesters of pregnancy and weekly in the third trimester of pregnancy. Changes in values during pregnancy may occur as a result of transient impairment of kidney and liver function from graft rejection and/or the development of complications of pregnancy. When the transplanted organ is stable, there are no pronounced negative fluctuations in these indicators.³¹

As the gestational age increases, the GFR increases, and there is a progressive decrease in the renal vascular resistance index (RI) as a result of an increase in the diastolic component of the blood flow. There is also a slight decrease in serum urea and creatinine levels. These changes in renal graft function are observed until the middle of the third trimester of pregnancy, when the intensity of renal blood flow decreases, resulting in a decrease in GFR and an increase in RI, which result in increased levels of creatinine and urea.

The dynamics of the functionality of the kidney transplant during pregnancy is explained by the physio-logical characteristics of the gestational process.³¹ Increased levels of chorionic gonadotropin, progesterone, and somatotropic hormone and physiological hypervolemia create conditions for increased renal blood flow and GFR. The decrease in blood flow in the kidneys, an increase in RI of the renal vessels, and a decrease in GFR before childbirth is explained by the activation of the sympathoadrenal and renin-angiotensin-aldosterone systems, resulting in an increase in adrenaline, active renin, and angiotensin in the blood and leading to an increase in peripheral vascular resistance.

Physiological changes during pregnancy are aimed at maintaining a high level of circulating blood volume to ensure adequate uteroplacental blood flow. These changes may be accompanied by a transient dysfunction of the kidney graft, although this does not require special medical correction.³¹ Additional information about the state of the vascular bed of the renal graft and the blood flow velocity can be obtained by Doppler ultrasonography of the renal vessels. Doppler ultrasonography can show blood flow velocity in the kidney and can allow the RI to be determined. The RI for normally functioning grafts is 0.8. Analyses of Doppler ultrasonography of renal transplants can reveal features of renal hemodynamics and indications of increases in its intensity as a result of increases in the diastolic component of blood flow with increasing gestational age (expressed as progressive decrease in RI). These changes are mostly shown during gestational age of 13 to 16 weeks. Immediately before delivery (at 37-38 weeks), there is an increase in peripheral vascular resistance and an increase in RI, which persists for 3 to 4 weeks after delivery.

An increase in RI of >0.8 is a prognostically unfavorable factor and may indicate the possible formation of transplant nephropathy, renal obstruction, pyelonephritis, or preeclampsia. Pregnancy in liver transplant recipients may be accompanied by a decrease in platelet levels, moderate increases in hepatic transaminases and bilirubin, and a decrease in albumin and prothrombin index values.

The stability of the transplanted solid organ largely depends on the adequacy of immunosuppressive therapy. In this regard, special attention is needed for any dose adjustment of immunosuppressive drugs used during pregnancy, with consideration of having minimal adverse reactions while maintaining an adequate level of immunosuppression and stability of the graft. All recipients of kidney and liver transplants during the gestation period should continue maintenance immunosuppressive therapy and glucocorticoids. Immunosuppression used during pregnancy should prevent graft rejection but minimize the risk of side effects.^32,33 Most modern immunosuppression regimens include calcineurin inhibitors (cyclosporine and tacrolimus). The latter is gradually becoming an increasingly common immunosuppressant and does not have an embryotoxic or teratogenic effect.^14,17,19 Optimal doses of calcineurin inhibitors should be used throughout the entire gestational period.³⁴ During pregnancy, side effects may be observed, which may be due to a high concentration of the drug. Adverse side effects can include an increase in the frequency of arterial hypertension and children with low birth weight. However, inadequate immunosuppression during pregnancy can lead to graft dysfunction and rejection episodes. Monitoring the blood concentrations of cyclosporine and tacrolimus during pregnancy can indicate their progressive decreased levels. However, decreases may occur from an increase in circulating blood volume and a physiological decrease in hematocrit during gestation.

Fluctuations in the concentration of immunosup-pressants in the blood may also occur from metabolic transformations and competitive relationships with prolactin and other hormones during the period of changed physiological and metabolic conditions. Thus, to avoid the development of graft dysfunction and acute and/or chronic rejection during pregnancy, constant dose adjustments are recommended in accordance with the concentration of the immunosuppressive drug in the blood and its therapeutic level.¹⁶

Monitoring of immunosuppressive drug levels should be conducted 1 to 2 times per month in the first and second trimesters and weekly in the third trimester of pregnancy. Our experiences showed that women who had timely dose adjustments did not have episodes of graft dysfunction during pregnancy. Rejection of the solid-organ transplant during pregnancy is quite rare but occurs with inadequate doses of immunosuppressants.^21,22 Calcineurin inhibitor levels in the blood are also subject to significant fluctuations in the postpartum period, which is explained by the prescription of specific inhibitors of prolactin secretion to puerpera with a kidney and liver transplant. This circumstance should be taken into account when adjusting dose levels after childbirth.¹⁶

An important indicator of the condition of the transplanted kidney is the proteinuria level. Proteinuria is considered as a risk factor for the development of chronic transplant nephropathy, as well as pregnancy complications (preeclampsia, arterial hypertension).¹⁶ During pregnancy, proteinuria slightly increases; by the end of the gestational period, it may exceed 0.5 g/L. Even with uncomplicated pregnancies, most kidney transplant recipients have proteinuria, which is due to an increase in the plasma flow index, the volume of which increases by more than 50%, stagnation in the kidneys, and increased pressure in the renal vein. Therefore, a moderately stable proteinuria level during pregnancy should not be considered a sign of progression of renal pathology, provided that it is not combined with arterial hypertension.

Arterial hypertension occurs in 25% to 40% of female solid-organ transplant recipients even before pregnancy.^16,23 Among the reasons for its development are the vasculotoxic effect of calcineurins, the hypertensive effect of corticosteroids, and the vasopressor effect of renal ischemia.^18,23 Our experiences showed a need for medical correction of hypertension through increased doses of antihypertensive drugs during pregnancy in 78% of kidney transplant recipients and in 40% of liver transplant recipients. Other studies showed higher frequency of hypertensive disorders (up to 85%) among pregnant women with a transplanted kidney.^9,12,13

During pregnancy, arterial hypertension aggravated by increasing proteinuria may indicate the development of preeclampsia.^1-3,23 Known clinical and laboratory changes in kidney transplant recipients include increased proteinuria, arterial hypertension, creatinine, and urea and decreased arterial blood flow from increases in the peripheral resistance of the vascular bed of the kidney. These factors may equally indicate a dysfunction of the transplanted kidney. A timely identification of the cause is needed for management of pregnancy and to determine the term of delivery. Often, only kidney biopsy data can establish an accurate diagnosis.

Among other complications of pregnancy in recipients of solid organs, anemia is often (up to 85%) observed,^12,16,17,19 the causes of which may be a decrease in the synthesis of erythropoietin, a side effect of taking immunosuppressants, beta blockers, or angiotensin-converting enzyme inhibitors (even before pregnancy), as well as the depletion of ferritin reserves, an increase in BCC and hemodilution, fluid retention due to increased secretion of antidiuretic hormone and aldosterone, an increase in iron requirements, and a lack of folic acid.⁴ With the ineffectiveness of traditional antianemic therapy, we have demonstrated a good therapeutic effect of the use of recombinant erythropoietin α,β. The effectiveness of treatment improves with the use of complex therapy with the inclusion of folic acid at a dose of up to 5 mg/day and cyanocobalamin at a dose of 1 to 2 mg/day. For kidney transplant recipients, one of the complications of the gestational period is pyelonephritis of the transplanted kidney.^2-4

Pyelonephritis is the most common infectious comp-lication during pregnancy in women with a transplanted kidney and occurs with a frequency of up to 60%.¹⁶ Prerequisites for the development of this complication may be physiological dilatation and hypokinesia of the urinary tract. To a greater extent, these processes are expressed in the second and third trimesters of pregnancy. After delivery, they gradually regress within 4 to 8 weeks. Pregnant women with a kidney transplant have additional causes for the development of gestational pyelonephritis: long-term immunosuppression and preexisting graft pyelonephritis. Specific factors that increase the risk of graft pyelonephritis during pregnancy include infection of the graft itself, vesicoureteral reflux, hypotension and catheterization of the bladder, and increased excretion of glucose in the urine, which is a nutrient medium for pathogens. Most often, urinary tract infections during pregnancy occur in women whose cause of kidney failure was pyelonephritis of their own kidneys, as well as previous transplant pyelonephritis. In the absence of characteristic clinical symptoms, the diagnostic criteria for pyelonephritis are leukocyturia and bacteriuria. If bacteriuria are detected, pregnant women with a transplanted kidney should be hospitalized for antibiotic therapy, taking into account the sensitivity of isolated microorganisms to antibacterial drugs. It is also necessary to consider the features of the pharmacokinetics of drugs, the possibility of embryotoxic and teratogenic effects, and the ability for the drugs to cross the placenta. Preference should be given to semi-synthetic penicillins and cephalosporins (II, III and IV generations). Antibiotics from these groups have varying degrees of permeability through the placenta and accumulation in the amniotic fluid and are devoid of embryotoxic and teratogenic properties, allowing them to be used during pregnancy.

Premature birth and the birth of low-birth-weight babies are complications that are also characteristic of this group of patients.¹⁵ The rate of preterm delivery has been shown to reach 82% among kidney transplant recipients and 50% in liver transplant recipients. Hypertensive complications were the main indications for early operative delivery. Pregnant women with organ transplants have a high probability of preterm birth (up to 50%), with frequency of fetal growth retardation syndrome reaching 20%.^5,10

Conclusions
Pregnancy after a kidney transplant often results in premature and low-birth-weight babies and should therefore be at “high risk.” In our experience, the development and growth of children after birth was good and age appropriate. All pregnancies were successful and resulted in the birth of a child. According to our data, pregnancy did not adversely affect graft function. Recommended maintenance immunosuppression in pregnant women with tacrolimus, azathioprine, and low-dose prednisone was safe. Good results were directly related to stable kidney function and absence of infections during pregnancy and the postpartum period, well-controlled hypertension and proteinuria, timely and correct dose adjustment of immunosuppressants, and duration of time from transplant to pregnancy of at least 1 year.

In general, the outcomes of pregnancy in patients with a transplanted kidney are favorable. Predictors of a favorable outcome of pregnancy are stable, satisfactory function of the graft, the absence of severe hypertension, pregnancy planning, and high discipline of the patient. The management of pregnancy for women with a kidney transplant should be carried out by a team of doctors of different specialties, including obstetrician-gynecologists, nephrologists, therapists, and transplant surgeons.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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