World J Nephrol Urol

World Journal of Nephrology and Urology, ISSN 1927-1239 print, 1927-1247 online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Nephrol Urol and Elmer Press Inc

Journal website http://www.wjnu.org

Review

Volume 7, Number 1, March 2018, pages 1-11

What We Do and Do Not Know About Women and Kidney Diseases; Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Women’s Day

Figure 1. Sex differences throughout the continuum of CKD care. SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; SS: systemic scleroderma; AKI: acute kidney injury; CKD: chronic kidney disease; AI: autoimmune; AVF: arteriovenous fistula; HD: hemodialysis; KT: kidney transplant.

Figure 2. Pregnancy and kidney function: complex interactions between two organs, the kidney and placenta. PE: preeclampsia; AKI: acute kidney injury; CKD: chronic kidney disease.

**Table 1.** Adverse Pregnancy Outcomes in Patients With Chronic Kidney Disease and in Their Offspring
Term	Definition	Main issues
SLE: systemic lupus erythematosus; AKI: acute kidney injury; GFR: glomerular filtration rate; sCR: serum creatinine; CKD: chronic kidney disease; LLAC: Lupus-like anticoagulant; PE-AKI: preeclampsia acute kidney injury; SGA: small for gestational age; IUGR: intrauterine growth restriction; MMF: mycophenolate mofetil; mTor: mechanistic target of rapamycin; ACEi: angiotensin-converting-enzyme inhibitor; ARBS: angiotensin II receptor blockers; PKD: polycystic kidney disease; CAKUT: congenital anomalies of the kidney and urinary tract; IgA: immunoglobulin A.
Maternal death	Death in pregnancy or within 1 week - 1 month postpartum	Too rare to be quantified, at least in highly resourced settings, where cases are in the setting of severe flares of immunologic diseases (SLE in primis). Still an issue in AKI; and in low resourced countries; not quantified in low-resourced countries, where it merges with dialysis need.
CKD progression	Decrease in GFR, rise in sCr, shift to a higher CKD stage	Differently assessed and estimated; may be linked to obstetric policy (anticipating delivery in the case of worsening of the kidney function); between 20% and 80% in advanced CKD. Probably not increased in early CKD stages.
Immunologic flares and neonatal SLE	Flares of immunologic diseases in pregnancy	Once thought to be increased in pregnancy, in particular in SLE, are probably risks in patients who start pregnancy with an active disease, or with a recent flare-up. Definition of a “safe” zone is not uniformly agreed; in quiescent, well controlled diseases do not appear to be increased with respect to non-pregnant, carefully-matched controls.
Transplant rejection	Acute rejection in pregnancy	Similar to SLE, rejection episodes are not increased with respect to matched controls; may be an issue in unplanned pregnancies, in unstable patients.
Abortion	Fetal loss, before 21 - 24 gestational weeks	May be increased in CKD, but data are scant. An issue in immunologic diseases (eventually, but not exclusively linked to the presence of LLAC) and in diabetic nephropathy.
Stillbirth	Delivery of a nonviable infant, after 21 - 24 gestational weeks	Probably not increased in early CKD, may be an issue in dialysis patients; when not linked to extreme prematurity, may specifically linked to SLE, immunologic diseases and diabetic nephropathy.
Perinatal death	Death within 1 week - 1 month from delivery	Usually a result of extreme prematurity, which bears a risk of respiratory distress, neonatal sepsis, cerebral hemorrhage.
Small, very small baby	A baby weighting < 2,500 - 1,500 g at birth	Has to be analyzed with respect to gestational age.
Preterm, early extremely preterm	Delivery before 37 - 34 or 28 completed gestational weeks	Increase in risk of preterm and early preterm delivery across CKD stages; extremely preterm may be an important issue in undiagnosed or late referred CKD and PE-AKI.
SGA (IUGR)	< 5th or < 10th centile for gestational age	Strictly and inversely related to pre-term delivery; SGA and IUGR are probably related to risk for hypertension, metabolic syndrome and CKD in adulthood.
Malformations	Any kind of malformations	Malformations are not increased in CKD patients not treated by teratogen drugs (MMF, mTor inhibitors, ACEi, ARBS); exception: diabetic nephropathy (attributed to diabetes); hereditary diseases, such as PKD, reflux nephropathy, CAKUT may be evident at birth.
Hereditary kidney diseases	Any kind of CKD	Several forms of CKD recognize a hereditary pattern or predisposition; besides PKD, reflux and CAKUT, Alport’s disease, IgA, kidney tubular disorders and mitochondrial diseases have a genetic background, usually evident in adulthood and not always clearly elucidated.
CKD - hypertension	Higher risk of hypertension and CKD in adulthood	Late maturation of nephrons results in a lower nephron number in preterm babies; the risks are probably higher in SGA-IUGR babies than in pre-term babies adequate for gestational age.
Other long-term issues	Developmental disorders	Mainly due to prematurity, cerebral hemorrhage or neonatal sepsis, are not specific of CKD, but is a threat in all preterm babies.

Table 1. Adverse Pregnancy Outcomes in Patients With Chronic Kidney Disease and in Their Offspring

Term

Definition

Main issues

SLE: systemic lupus erythematosus; AKI: acute kidney injury; GFR: glomerular filtration rate; sCR: serum creatinine; CKD: chronic kidney disease; LLAC: Lupus-like anticoagulant; PE-AKI: preeclampsia acute kidney injury; SGA: small for gestational age; IUGR: intrauterine growth restriction; MMF: mycophenolate mofetil; mTor: mechanistic target of rapamycin; ACEi: angiotensin-converting-enzyme inhibitor; ARBS: angiotensin II receptor blockers; PKD: polycystic kidney disease; CAKUT: congenital anomalies of the kidney and urinary tract; IgA: immunoglobulin A.

Maternal death

Death in pregnancy or within 1 week - 1 month postpartum

Too rare to be quantified, at least in highly resourced settings, where cases are in the setting of severe flares of immunologic diseases (SLE in primis). Still an issue in AKI; and in low resourced countries; not quantified in low-resourced countries, where it merges with dialysis need.

CKD progression

Decrease in GFR, rise in sCr, shift to a higher CKD stage

Differently assessed and estimated; may be linked to obstetric policy (anticipating delivery in the case of worsening of the kidney function); between 20% and 80% in advanced CKD. Probably not increased in early CKD stages.

Immunologic flares and neonatal SLE

Flares of immunologic diseases in pregnancy

Once thought to be increased in pregnancy, in particular in SLE, are probably risks in patients who start pregnancy with an active disease, or with a recent flare-up. Definition of a “safe” zone is not uniformly agreed; in quiescent, well controlled diseases do not appear to be increased with respect to non-pregnant, carefully-matched controls.

Transplant rejection

Acute rejection in pregnancy

Similar to SLE, rejection episodes are not increased with respect to matched controls; may be an issue in unplanned pregnancies, in unstable patients.

Abortion

Fetal loss, before 21 - 24 gestational weeks

May be increased in CKD, but data are scant. An issue in immunologic diseases (eventually, but not exclusively linked to the presence of LLAC) and in diabetic nephropathy.

Stillbirth

Delivery of a nonviable infant, after 21 - 24 gestational weeks

Probably not increased in early CKD, may be an issue in dialysis patients; when not linked to extreme prematurity, may specifically linked to SLE, immunologic diseases and diabetic nephropathy.

Perinatal death

Death within 1 week - 1 month from delivery

Usually a result of extreme prematurity, which bears a risk of respiratory distress, neonatal sepsis, cerebral hemorrhage.

Small, very small baby

A baby weighting < 2,500 - 1,500 g at birth

Has to be analyzed with respect to gestational age.

Preterm, early extremely preterm

Delivery before 37 - 34 or 28 completed gestational weeks

Increase in risk of preterm and early preterm delivery across CKD stages; extremely preterm may be an important issue in undiagnosed or late referred CKD and PE-AKI.

SGA (IUGR)

< 5th or < 10th centile for gestational age

Strictly and inversely related to pre-term delivery; SGA and IUGR are probably related to risk for hypertension, metabolic syndrome and CKD in adulthood.

Malformations

Any kind of malformations

Malformations are not increased in CKD patients not treated by teratogen drugs (MMF, mTor inhibitors, ACEi, ARBS); exception: diabetic nephropathy (attributed to diabetes); hereditary diseases, such as PKD, reflux nephropathy, CAKUT may be evident at birth.

Hereditary kidney diseases

Any kind of CKD

Several forms of CKD recognize a hereditary pattern or predisposition; besides PKD, reflux and CAKUT, Alport’s disease, IgA, kidney tubular disorders and mitochondrial diseases have a genetic background, usually evident in adulthood and not always clearly elucidated.

CKD - hypertension

Higher risk of hypertension and CKD in adulthood

Late maturation of nephrons results in a lower nephron number in preterm babies; the risks are probably higher in SGA-IUGR babies than in pre-term babies adequate for gestational age.

Other long-term issues

Developmental disorders

Mainly due to prematurity, cerebral hemorrhage or neonatal sepsis, are not specific of CKD, but is a threat in all preterm babies.

**Table 2.** Sex Differences in the Incidence and Severity of Autoimmune Diseases
	SLE	RA	SS
SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; SS: systemic scleroderma.
Peak incidence	Reproductive age	Perimenopausal	After 50 - 60 years
Female/male ratio	Peak 15:1	Peak 4:1	Peak 14:1
	Total 9:1	After 60 years 1:1	Total 3:1
Influence of estrogen	High levels	Negative	Positive	?
	Low levels	?	Negative	Negative

Table 2. Sex Differences in the Incidence and Severity of Autoimmune Diseases

SLE

SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; SS: systemic scleroderma.

Peak incidence

Reproductive age

Perimenopausal

After 50 - 60 years

Female/male ratio

Peak 15:1

Peak 4:1

Peak 14:1

Total 9:1

After 60 years 1:1

Total 3:1

Influence of estrogen

High levels

Negative

Positive

Low levels

Negative