Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Maternal Origins of Neonatal Infections: What Do Obstetrician-Gynecologist Should/Could Do?

Neonatal infections are responsible for 20% of neonatal deaths yearly. In this review, we focused on the origins of the commoner neonatal infections, and we define the role of obstetricians. Regarding group B Streptococcus, a key measure for the prevention of neonatal infection is the vaginal-rectal culture screening at term pregnancy. Intravenous penicillin is the first-line prophylaxis at the start of labor, with intravenous ampicillin as an alternative. First-generation cephalosporins or clindamycin are recommended in case of penicillin allergy. Concerning urinary tract infections (UTIs), guidelines recommend complete urinalysis and urine culture in the first trimester of pregnancy for the screening of asymptomatic bacteriuria. For lower UTIs, guidelines recommend nitrofurantoin as first-choice antibiotic. Amoxicillin or cefalexin are second-line antibiotics. For upper UTIs, guidelines recommend cephalexin per os as first line. Candida spp. colonization affects 20% of pregnant women; however, congenital fetal candidosis and Candida amnionitis are rare. First-line treatment in case of symptomatic vaginitis during pregnancy or asymptomatic colonization during the third trimester is vaginal clotrimazole. Fluconazole is not approved in pregnancy, especially during the first trimester. Genital mycoplasmas colonization during pregnancy is usually asymptomatic and associated with bacterial vaginosis. Colonization is related to neonatal respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), pneumonia, chorioamnionitis, and sepsis. Macrolides are the first-line treatment along with lactobacillus supplementation. In cases of preterm premature rupture of membranes or preterm labor, ceftriaxone, clarithromycin, and metronidazole are required to prevent intra-amniotic infection. Intra-amniotic infection affects 1 to 5% of deliveries at term and one-third of preterm ones and is associated with perinatal death, early-onset neonatal sepsis, RDS, BPD, pneumonia, meningitis, and prematurity-related diseases. Guidelines recommend a combination of ampicillin and gentamicin, and in case of caesarean section, an additional dose of clindamycin or metronidazole is required. In conclusion, obstetricians should be aware that the treatment of maternal infection during pregnancy can prevent potentially lethal infections in the newborn. KEY POINTS: · Part of neonatal infections starts from maternal infections that must be treated during pregnancy.. · Streptococcus group B and asymptomatic bacteriuria should be investigated in pregnancy and treated.. · Mycoplasma and ureaplasma vaginal colonization during pregnancy is related to negative neonatal outcomes..

Consecutive chorioangiomas in the same pregnancy: A clinical case and review of literature.

Background and Aims: Aetiopathogenesis of chorioangioma is already unknown. Among the risk factors, hypoxia, environmental and genetic factors are believed to induce the overexpression of angiogenic cytokines promoting vascular proliferation. We reported a case of prenatally diagnosed 67 mm-wide placental chorioangioma, which occurred at 32 weeks of gestational age, infarcted, and followed by the onset of a second infarcted chorioangioma at 35 weeks of gestational age. Besides, we discussed the hypothesis of chorioangioma aetiopathogenesis and behavior through a literature summary. Methods: We carried out a literature search of chorioangioma cases without a time interval. Therefore, we carried out a literature summary on chorioangioma risk factors and etiology, by selecting articles within a time interval from 1995 to 2021. Results: This is the first case of two consecutive chorioangiomas in the same pregnancy published in the literature. We found a possible genetic predisposition in women developing chorioangioma while infarction may be related to the abnormal structure of tumor vessels. The onset of a second lesion could reflect hypoxic stimuli following infarction and involves hypoxia-induced factor-1alpha, vascular endothelial growth factor, transforming growth factor-beta, and soluble Fms-like tyrosine kinase-1 pathways. Chorangiosis can be coexistent and may reflect a mutual etiology in susceptible individuals. Conclusion: In a predisposed placenta, that previously generated a chorioangioma, infarction of the chorioangioma should not represent a sign for pregnancy termination, but a marker for closer monitoring to early detect the possible onset of a second chorioangioma and a higher risk of umbilical cord thrombosis.

History of Preeclampsia in Patients Undergoing a Kidney Biopsy: A Biphasic, Multiple-Hit Pathogenic Hypothesis.

Introduction: It is not fully elucidated whether preeclampsia (PE) is a marker or a cause of chronic kidney disease (CKD). To test the hypothesis of a biphasic relationship between PE and CKD, we assessed PE prevalence in women who underwent a kidney biopsy. Methods: This retrospective, observational study recruited patients who underwent a kidney biopsy after delivery in 2014 to 2019 in 3 Italian Centers (Cagliari, Bari, Messina); low-risk pregnancies observed in Cagliari served as controls. A history of PE was assessed on the clinical charts and by phone interview. Results: In the biopsy cohort (379 pregnancies, 205 patients; 38 PE in 32 patients), kidney biopsy shows clustering in the first 5 years after PE (11 of 32). Pre-existing CKD was detected in 8 of 11 of these cases. Focal-segmental glomerulosclerosis (FSGS) and complex lesions were found in 12 of 32 biopsies. The odds ratio (OR) of having had a PE episode, compared with 561 low-risk pregnancies, was 10.071 (95% CI: 4.859-20.875; P < 0.001); multiparity maintained a protective effect (OR: 0.208). The delivery-to-biopsy time was significantly shorter in women with PE, both considering the first or the last PE versus the first or last delivery in patients with or without PE episodes. The characteristics of PE did not differ as compared with low-risk controls. Conclusion: Within the limitation of the retrospective design, our study, quantifying the association between needing a kidney biopsy and history of PE, suggests a biphasic pattern, with a peak in the first 5 years after delivery (probably due to pre-existing diseases) and a later increase, suggesting that PE may have later played as one hit in a multiple-hit pathogenesis.

Contraception in chronic kidney disease: a best practice position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology.

Even though fertility is reduced, conception and delivery are possible in all stages of CKD. While successful planned pregnancies are increasing, an unwanted pregnancy may have long-lasting deleterious effects, hence the importance of birth control, an issue often disregarded in clinical practice. The evidence summarized in this position statement is mainly derived from the overall population, or other patient categories, in the lack of guidelines specifically addressed to CKD. Oestroprogestagents can be used in early, non-proteinuric CKD, excluding SLE and immunologic disorders, at high risk of thromboembolism and hypertension. Conversely, progestin only is generally safe and its main side effect is intramestrual spotting. Non-medicated intrauterine devices are a good alternative; their use needs to be carefully evaluated in patients at a high risk of pelvic infection, even though the degree of risk remains controversial. Barrier methods, relatively efficacious when correctly used, have few risks, and condoms are the only contraceptives that protect against sexually transmitted diseases. Surgical sterilization is rarely used also because of the risks surgery involves; it is not definitely contraindicated, and may be considered in selected cases. Emergency contraception with high-dose progestins or intrauterine devices is not contraindicated but should be avoided whenever possible, even if far preferable to abortion. Surgical abortion is invasive, but experience with medical abortion in CKD is still limited, especially in the late stages of the disease. In summary, personalized contraception is feasible, safe and should be offered to all CKD women of childbearing age who do not want to get pregnant.

Risk of Preeclampsia and Adverse Pregnancy Outcomes after Heterologous Egg Donation: Hypothesizing a Role for Kidney Function and Comorbidity.

BACKGROUND AND OBJECTIVES: Preeclampsia (PE) is a risk factor for kidney diseases; egg-donation (ED) increasingly used for overcoming fertility reduction, is a risk factor for PE. CKD is also a risk factor for PE. However, kidney function is not routinely assessed in ED pregnancies. Objective of the study is seeking to assess the importance of kidney function and maternal comorbidity in ED pregnancies. DESIGN: retrospective observational study from clinical charts. SETTING: Sant'Anna Hospital, Turin, Italy (over 7000 deliveries per year). SELECTION: cases: 296 singleton pregnancies from ED (gestation > 24 weeks), who delivered January 2008-February 2019. Controls were selected from the TOrino Cagliari Observational Study (1407 low-risk singleton pregnancies 2009-2016). MEASUREMENTS: Standard descriptive analysis. Logistic multiple regression analysis tested: PE; pregnancy-induced hypertension; preterm delivery; small for gestational age; explicatory variables: age; BMI; parity; comorbidity (kidney diseases; immunologic diseases; thyroid diseases; other). Delivery over time was analyzed according to Kaplan Meier; ROC (Relative Operating Characteristic) curves were tested for PE and pre-term delivery, employing serum creatinine and e-GFR as continuous variables. The analysis was performed with SPSS v.14.0 and MedCalc v.18. RESULTS: In keeping with ED indications, maternal age was high (44 years). Comorbidity was common: at least one potential comorbid factor was found in about 40% of the cases (kidney disease: 3.7%, immunologic 6.4%, thyroid disease 18.9%, other-including hypertension, previous neoplasia and all other relevant diseases-10.8%). No difference in age, parity and BMI is observed in ED women with and without comorbidity. Patients with baseline renal disease or "other" comorbidity had a higher risk of developing PE or preterm delivery after ED. PE was recorded in 23% vs. 9%, OR: 2.513 (CI 1.066-5.923; p = 0.039); preterm delivery: 30.2% vs. 14%, OR 2.565 (CI: 1.198-5.488; p = 0.044). Limiting the analysis to 124 cases (41.9%) with available serum creatinine measurement, higher serum creatinine (dichotomised at the median: 0.67 mg/dL) was correlated with risk of PE (multivariate OR 17.277 (CI: 5.125-58.238)) and preterm delivery (multivariate OR 2.545 (CI: 1.100-5.892). CONCLUSIONS: Within the limits of a retrospective analysis, this study suggests that the risk of PE after ED is modulated by comorbidity. While the cause effect relationship is difficult to ascertain, the relationship between serum creatinine and outcomes suggests that more attention is needed to baseline kidney function and comorbidity.

A best-practice position statement on pregnancy after kidney transplantation: focusing on the unsolved questions. The Kidney and Pregnancy Study Group of the Italian Society of Nephrology.

Kidney transplantation (KT) is often considered to be the method best able to restore fertility in a woman with chronic kidney disease (CKD). However, pregnancies in KT are not devoid of risks (in particular prematurity, small for gestational age babies, and the hypertensive disorders of pregnancy). An ideal profile of the potential KT mother includes "normal" or "good" kidney function (usually defined as glomerular filtration rate, GFR ≥ 60 ml/min), scant or no proteinuria (usually defined as below 500 mg/dl), normal or well controlled blood pressure (one drug only and no sign of end-organ damage), no recent acute rejection, good compliance and low-dose immunosuppression, without the use of potentially teratogen drugs (mycophenolic acid and m-Tor inhibitors) and an interval of at least 1-2 years after transplantation. In this setting, there is little if any risk of worsening of the kidney function. Less is known about how to manage "non-ideal" situations, such as a pregnancy a short time after KT, or one in the context of hypertension or a failing kidney. The aim of this position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology is to review the literature and discuss what is known about the clinical management of CKD after KT, with particular attention to women who start a pregnancy in non-ideal conditions. While the experience in such cases is limited, the risks of worsening the renal function are probably higher in cases with markedly reduced kidney function, and in the presence of proteinuria. Well-controlled hypertension alone seems less relevant for outcomes, even if its effect is probably multiplicative if combined with low GFR and proteinuria. As in other settings of kidney disease, superimposed preeclampsia (PE) is differently defined and this impairs calculating its real incidence. No specific difference between non-teratogen immunosuppressive drugs has been shown, but calcineurin inhibitors have been associated with foetal growth restriction and low birth weight. The clinical choices in cases at high risk for malformations or kidney function impairment (pregnancies under mycophenolic acid or with severe kidney-function impairment) require merging clinical and ethical approaches in which, beside the mother and child dyad, the grafted kidney is a crucial "third element".

Pregnancy, Proteinuria, Plant-Based Supplemented Diets and Focal Segmental Glomerulosclerosis: A Report on Three Cases and Critical Appraisal of the Literature.

Chronic kidney disease (CKD) is increasingly recognized in pregnant patients. Three characteristics are associated with a risk of preterm delivery or small for gestational age babies; kidney function reduction, hypertension, and proteinuria. In pregnancy, the anti-proteinuric agents (ACE-angiotensin converting enzyme-inhibitors or ARBS -angiotensin receptor blockers) have to be discontinued for their potential teratogenicity, and there is no validated approach to control proteinuria. Furthermore, proteinuria usually increases as an effect of therapeutic changes and pregnancy-induced hyperfiltration. Based on a favourable effect of low-protein diets on proteinuria and advanced CKD, our group developed a moderately protein-restricted vegan-vegetarian diet tsupplemented with ketoacids and aminoacids for pregnant patients. This report describes the results obtained in three pregnant patients with normal renal function, nephrotic or sub-nephrotic proteinuria, and biopsy proven diagnosis of focal segmental glomerulosclerosis, a renal lesion in which hyperfiltration is considered of pivotal importance (case 1: GFR (glomerular filtration rate): 103 mL/min; proteinuria 2.1 g/day; albumin 3.2 g/dL; case 2: GFR 86 mL/min, proteinuria 3.03 g/day, albumin 3.4 g/dL; case 3: GFR 142 mL/min, proteinuria 6.3 g/day, albumin 3.23 g/dL). The moderately restricted diet allowed a stabilisation of proteinuria in two cases and a decrease in one. No significant changes in serum creatinine and serum albumin were observed. The three babies were born at term (38 weeks + 3 days, female, weight 3180 g-62th centile; 38 weeks + 2 days, female, weight 3300 g-75th centile; male, 38 weeks + 1 day; 2770 g-8th centile), thus reassuring us of the safety of the diet. In summary, based on these three cases studies and a review of the literature, we suggest that a moderately protein-restricted, supplemented, plant-based diet might contribute to controlling proteinuria in pregnant CKD women with focal segmental glomerulosclerosis. However further studies are warranted to confirm the potential value of such a treatment strategy.

Is It Possible to Differentiate Chronic Kidney Disease and Preeclampsia by means of New and Old Biomarkers? A Prospective Study.

OBJECTIVE: Chronic kidney disease (CKD) and preeclampsia (PE) may both present with hypertension and proteinuria in pregnancy. Our objective is to test the possibility of distinguishing CKD from PE by means of uteroplacental flows and maternal circulating sFlt-1/PlGF ratio. DESIGN: Prospective analysis. POPULATION: Seventy-six patients (35 CKD, 24 PE, and 17 other hypertensive disorders), with at least one sFlt-1/PlGF and Doppler evaluation after the 20th gestational week. METHODS: Maternal sFlt-1-PlGF were determined by immunoassays. Abnormal uterine artery Doppler was defined as resistance index ≥ 0.58. Umbilical Doppler was defined with gestational-age-adjusted Pulsatility Index. Clinical diagnosis was considered as reference. Performance of Doppler study was assessed by sensitivity analysis; sFlt-1/PlGF cut-off values were determined by ROC curves. RESULTS: The lowest sFlt-1/PlGF ratio (8.29) was detected in CKD, the highest in PE (317.32) (P < 0.001). Uteroplacental flows were mostly preserved in CKD patients in contrast to PE (P < 0.001). ROC analysis suggested two cut-points: sFlt-1/PlGF ≥ 32.81 (sensitivity 82.93%; specificity 91.43%) and sFlt-1/PlGF ≥ 78.75 (sensitivity 62.89%, specificity 97.14%). Specificity reached 100% at sFlt-1/PlGF ≥ 142.21 (sensitivity: 48.8%). Early-preterm delivery was associated with higher sFlt-1/PlGF ratio and abnormal uteroplacental flows relative to late-preterm and term deliveries. CONCLUSIONS: sFlt-1/PlGF ratio and uteroplacental flows significantly correlated with PE or CKD and preterm delivery.

Pregnancy in Chronic Kidney Disease: questions and answers in a changing panorama.

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.

Severe diabetic nephropathy in type 1 diabetes and pregnancy--a case series.

BACKGROUND: Diabetes and nephropathy are important challenges during pregnancy, increasingly encountered because of the advances in maternal-fetal care. AIM: To evaluate the maternal and fetal outcomes recorded in "severe" diabetic nephropathy in type 1 diabetic patients referred to nephrological healtcare. METHODS: The study was performed in an outpatient unit dedicated to kidney diseases in pregnancy (with joint nephrological and obstetric follow-up and strict cooperation with the diabetes unit). 383 pregnancies were referred to the outpatient unit in 2000-2012, 14 of which were complicated by type 1 diabetes. The report includes 12 deliveries, including 2 pregnancies in 1 patient; one twin pregnancy; 2 spontaneous abortions were not included. All cases had long-standing type 1 diabetes (median of 21 (15-31) years), relatively high median age (35 (29-40) years) and end-organ damage (all patients presented laser-treated retinopathy and half of them clinical neuropathy). Median glomerular filtration rate (GFR) at referral was 67 ml/min (48-122.6), proteinuria was 1.6 g/day (0.1-6.3 g/day). RESULTS: Proteinuria steeply increased in 11/12 patients, reaching the nephrotic range in nine (6 above 5 g/day). One patient increased by 2 chronic kidney disease (CKD) stages. Support therapy included blood pressure and diabetes control, bed rest, and moderate protein restriction. All children were preterm (7 early preterm); early spontaneous labor occurred in 4/12 patients. All singletons were appropriate for gestational age and developed normally after birth. The male twin child died 6 days after birth (after surgery for great vessel transposition). CONCLUSIONS: Diabetic patients with severe diabetic nephropathy are still present a considerable challenge. Therefore, further investigations are required, particularly on proteinuria management and the occurrence of spontaneous labor.

Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers.

Preeclampsia, affecting 5-8% of pregnancies, is the main cause of fetal-maternal mortality and morbidity. The differential diagnosis with chronic kidney disease (CKD) is a challenge owing to the overlapping clinical features. No biomarker has been found to discriminate between the two conditions. Here, we tested whether maternal serum levels of placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1), markers of preeclampsia, could be used to discriminate between 34 patients with preeclampsia, 23 patients with CKD during pregnancy, and 38 healthy pregnant women. Serum levels of PlGF and sFlt-1 were determined during the third trimester by commercially available immunoassays. In preeclampsia, sFlt-1 levels were significantly increased in comparison with that in CKD and in the control women. Serum levels of PlGF in preeclampsia were significantly decreased relative to both controls and patients with CKD. The sFlt-1 to PlGF ratio was significantly increased in preeclampsia (median 436) compared with controls (median 9.4) and CKD (median 4.0). No differences were found between controls and patients with CKD. Thus, our study suggests that it is possible to discriminate between preeclampsia and CKD during pregnancy by determining maternal serum levels of sFlt-1 and PlGF and their ratio.

Metaplastic breast carcinoma: pathology and clinical outcome.

Metaplastic breast carcinomas are rare neoplasms showing both carcinomatous and sarcomatous elements. In this report we describe eleven cases of metaplastic breast carcinoma focusing on pathological features and the clinical behaviour of six patients with breast carcinoma with chondroid metaplasia (MCC). We collected eleven cases from 1996 to 2001: immunohistochemical tests were performed in order to obtain data on estrogen and progesterone receptors and the production of p53 gene and HER/2 neu. Neoangiogenesis was studied counting vessels immunohistochemically-stained with CD31 antibody. Six cases showed chondroid metaplasia, three cases were spindle cell carcinoma and two were metaplastic squamous carcinoma. The majority of patients (64%) had pT2 tumors without axillary node metastases: only two cases with spindle or squamous metaplasia showed nodal involvement. Fifty percent of MCC were pT1b-c tumors: no axillary metastases were observed. Vascular invasion was observed in all squamous and spindle cell types and in 66% of MCC: estrogen and progesterone receptors were absent in 90% of the tumors. Immunohistochemical staining for HER2/neu was detected in 72% of spindle cell and squamous carcinomas and in 33% of MCC. Three cases staining highly for p53 were chondroid carcinomas: the staining was uniform both in carcinomatous and in sarcomatous tissue. The majority of metaplastic carcinomas had high angionesis. One patient with a chondroid metaplastic carcinoma was found to be a carrier of a BRCA1 mutation similar to the one responsible for sickle cell disease, possibly altering the spatial structure of the gene product. Only six patients had follow-up periods longer than 36 months: five women were alive and disease-free: one patient with pT2N1 squamous metaplastic carcinoma died of disease 14 months after diagnosis. The six women with MCC were alive and disease-free. Surgical and adjuvant treatment should follow the guidelines for the other most common breast cancers even if the need for chemotherapy is unknown due to the absence of large series randomized or observational data.