Maternal Chronic Kidney Disease Research Articles

Protective Role of Taurine on Rat Offspring Hypertension in the Setting of Maternal Chronic Kidney Disease.

Taurine is a natural antioxidant with antihypertensive properties. Maternal chronic kidney disease (CKD) has an impact on renal programming and increases the risk of offspring hypertension in later life. The underlying mechanisms cover oxidative stress, a dysregulated hydrogen sulfide (H2S) system, dysbiotic gut microbiota, and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether perinatal taurine administration enables us to prevent high blood pressure (BP) in offspring complicated by maternal CKD. Before mating, CKD was induced through feeding chow containing 0.5% adenine for 3 weeks. Taurine was administered (3% in drinking water) during gestation and lactation. Four groups of male offspring were used (n = 8/group): controls, CKD, taurine-treated control rats, and taurine-treated rats with CKD. Taurine treatment significantly reduced BP in male offspring born to mothers with CKD. The beneficial effects of perinatal taurine treatment were attributed to an augmented H2S pathway, rebalance of aberrant RAAS activation, and gut microbiota alterations. In summary, our results not only deepen our knowledge of the mechanisms underlying maternal CKD-induced offspring hypertension but also afford us the impetus to consider taurine-based intervention as a promising preventive approach for future clinical translation.

Impact of near-miss event during pregnancy and childbirth on maternal health at 12 months.

To assess the impact of maternal near-miss on late maternal death and the prevalence of hypertension or chronic kidney disease (CKD) and mental health problems at 12 months of follow up. This prospective cohort study was conducted in a tertiary hospital in the southeastern region of India from May 2018 to August 2019, enrolling those with maternal near-miss and with follow up for 12 months. The primary outcomes were incidence of late maternal deaths and prevalence of hypertension and CKD during follow up. Incidence of maternal near miss was 6.7 per 1000 live births. Among those who had a near miss, late maternal deaths occurred in 7.2% (95% confidence interval [CI] 3.1%-11.3%); prevalence of CKD was 23.0% (95% CI 16.2%-29.8%), and of hypertension was 56.2% (95% CI 50.5%-66.5%) and only two women had depression on follow up. After adjusting for age, parity, socioeconomic status, gestational age at delivery, hemoglobin levels, and perinatal loss, only serum creatinine was independently associated with late maternal death and CKD on follow up. Women who survive a life-threatening complication during pregnancy and childbirth are at increased risk of mortality and one or more long-term sequelae contributing to the non-communicable disease burden. A policy shift to increase postpartum follow-up duration, following a high-risk targeted approach after a near-miss event, is needed.

Protection by Means of Perinatal Oral Sodium Thiosulfate Administration against Offspring Hypertension in a Rat Model of Maternal Chronic Kidney Disease.

Hydrogen sulfide (H2S) and related reactive sulfur species are implicated in chronic kidney disease (CKD) and hypertension. Offspring born to CKD-afflicted mothers could develop hypertension coinciding with disrupted H2S and nitric oxide (NO) signaling pathways as well as gut microbiota. Thiosulfate, a precursor of H2S and an antioxidant, has shown anti-hypertensive effects. This study aimed to investigate the protective effects of sodium thiosulfate (STS) in a rat model of maternal CKD-induced hypertension. Before mating, CKD was induced through feeding 0.5% adenine chow for 3 weeks. Mother rats were given a vehicle or STS at a dosage of 2 g/kg/day in drinking water throughout gestation and lactation. Perinatal STS treatment protected 12-week-old offspring from maternal CKD-primed hypertension. The beneficial effects of STS could partially be explained by the enhancement of both H2S and NO signaling pathways and alterations in gut microbiota. Not only increasing beneficial microbes but maternal STS treatment also mediates several hypertension-associated intestinal bacteria. In conclusion, perinatal treatment with STS improves maternal CKD-primed offspring hypertension, suggesting that early-life RSS-targeting interventions have potential preventive and therapeutic benefits, awaiting future translational research.

Feminizing care pathways: Mixed-methods study of reproductive options, decision making, pregnancy, post-natal care and parenting amongst women with kidney disease.

To identify the needs, experiences and preferences of women with kidney disease in relation to their reproductive health to inform development of shared decision-making interventions. UK-wide mixed-methods convergent design (Sep 20-Aug 21). Online questionnaire (n = 431) with validated components. Purposively sampled semi-structured interviews (n = 30). Patient and public input throughout. Kidney disease was associated with defeminization, negatively affecting current (sexual) relationships and perceptions of future life goals. There was little evidence that shared decision making was taking place. Unplanned pregnancies were common, sometimes influenced by poor care and support and complicated systems. Reasons for (not) wanting children varied. Complicated pregnancies and miscarriages were common. Women often felt that it was more important to be a "good mother" than to address their health needs, which were often unmet and unrecognized. Impacts of pregnancy on disease and options for alternates to pregnancy were not well understood. The needs and reproductive priorities of women are frequently overshadowed by their kidney disease. High-quality shared decision-making interventions need to be embedded as routine in a feminized care pathway that includes reproductive health. Research is needed in parallel to examine the effectiveness of interventions and address inequalities. We do not fully understand the expectations, needs, experiences and preferences of women with kidney disease for planning and starting a family or deciding not to have children. Women lack the knowledge, resources and opportunities to have high-quality conversations with their healthcare professionals. Decisions are highly personal and related to a number of health, social and cultural factors; individualized approaches to care are essential. Healthcare services need to be redesigned to ensure that women are able to make informed choices about pregnancy and alternative routes to becoming a parent. The original proposal for this research came from listening to the experiences of women in clinic who reported unmet needs and detailed experiences of their pregnancies (positive and negative). A patient group was involved in developing the funding application and helped to refine the objectives by sharing their experiences. Two women who are mothers living with kidney disease were co-opted as core members of the research team. We hosted an interim findings event and invited patients and wider support services (adoption, fertility, surrogacy, education and maternal chronic kidney disease clinics) from across the UK to attend. We followed the UK national standards for patient and public involvement throughout.

Iodomethylcholine Inhibits Trimethylamine-N-Oxide Production and Averts Maternal Chronic Kidney Disease-Programmed Offspring Hypertension.

Chronic kidney disease (CKD) affects 10% of the global population, including pregnant women. Adverse maternal conditions determine the developmental programming of many diseases later in life. We previously demonstrated that adult rat offspring born to dams with CKD developed hypertension and renal hypertrophy. Trimethylamine-N-oxide (TMAO), a uremic toxin derived from the gut microbiota, has been linked to hypertension. This study assesses the effects of TMAO inhibition by iodomethylcholine (IMC) treatment on offspring hypertension programmed by maternal CKD. Female rats were fed either a control or a 0.5% adenine diet before conception, with or without IMC treatment during pregnancy and lactation. Maternal IMC treatment averted maternal CKD-primed offspring hypertension and renal hypertrophy in 12-week-old offspring. Offspring hypertension is associated with increases in the plasma TMAO concentration and oxidative stress and shifts in gut microbiota. The beneficial effects of IMC are related to a reduction in TMAO; increases in genera Acetatifactor, Bifidobacterium, and Eubacterium; and decreases in genera Phocacecola and Bacteroides. Our findings afford insights into the targeting of the gut microbiota to deplete TMAO production, with therapeutic potential for the prevention of offspring hypertension programmed by maternal CKD, although these results still need further clinical translation.

Perinatal Garlic Oil Supplementation Averts Rat Offspring Hypertension Programmed by Maternal Chronic Kidney Disease

Garlic (Allium sativum) is a functional food, having hydrogen sulfide (H2S)-releasing capacity, which exhibits considerable effects on hypertension and gut microbiota. H2S is strongly associated with hypertension and chronic kidney disease (CKD). Maternal CKD leads to hypertension in adult rat progeny, which was linked to disruption of the gut microbiota. This study validated the benefits of perinatal garlic oil supplementation against offspring hypertension induced by maternal CKD via modulation of H2S signaling, nitric oxide (NO), and the gut microbiota. Before pregnancy, female rats received a 0.5% adenine diet for 3 weeks to develop an animal model to mimic human CKD. Garlic oil (100 mg/kg/day) or vehicle was administered to pregnant rats by oral gavage during gestation and lactation. Perinatal garlic oil supplementation protected against maternal CKD-induced hypertension in offspring at 12 weeks of age. The beneficial effects of garlic oil are associated with enhanced H2S signaling, increased NO bioavailability, and shifts in gut microbiota. Perinatal garlic oil supplementation reduces abundance of genera Variovorax, Nocardia, Sphingomonas, and Rhodococcus. Our findings provide insight into the role of early H2S-targeted intervention as a preventive strategy in hypertension for further translational research.

Perinatal Propionate Supplementation Protects Adult Male Offspring from Maternal Chronic Kidney Disease-Induced Hypertension.

Emerging evidence supports that early-life disturbance of gut microbiota has an impact on adult disease in later life. Offspring hypertension can be programmed by maternal chronic kidney disease (CKD). Conversely, perinatal use of gut microbiota-targeted therapy has been implemented to reverse programming processes and prevent hypertension. Short-chain fatty acids (SCFAs), the major gut microbiota-derived metabolites, can be applied as postbiotics. Propionate, one of predominant SCFAs, has been shown to have antihypertensive property. We examined whether perinatal propionate supplementation can prevent offspring hypertension induced by maternal CKD. CKD was induced by chow supplemented with 0.5% adenine for 3 weeks before pregnancy. Propionate (P) was supplemented at 200 mmol/L in drinking water during pregnancy and lactation. Male offspring were divided into four groups (n = 7–8/group): control, CKD, control+propionate (CP), and CKD+propionate (CKDP). Maternal CKD-induced offspring hypertension was reversed by perinatal propionate supplementation. The protective effects of perinatal propionate treatment were related to increased propionate-generating bacteria Clostridium spp. and plasma propionate level, increased expression of renal G protein-coupled receptor 41 (GPR41, a SCFA receptor), augmentation of α-diversity, and shifts in gut microbiota composition. In summary, our results highlight that maternal CKD-induced offspring hypertension can be prevented by the use of gut microbial metabolite SCFAs in early life, which could shed light on the prevention of the current hypertension pandemic.

MO078: Dietary Supplementation with Cysteine During Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulphide and Microbiota-Derived Tryptophan Metabolites

Abstract BACKGROUND AND AIMS Maternal chronic kidney disease (CKD) is linked to offspring hypertension. Gut microbiome and its tryptophan metabolites, nitric oxide (NO) and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulphide (H2S) has shown antihypertensive effect. Our objective was to test whether L- or D-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and explored the protective mechanisms. METHOD CKD was induced in pregnant Sprague-Dawley rats by a 0.5% adenine diet for 3 weeks. L- or D-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8/group). RESULTS Maternal CKD-induced hypertension was similarly prevented by L- or D-cysteine supplementation. The protective effects of L- and D-cysteine are related to reducing oxidative stress, rebalancing the RAS and reshaping the gut microbiome. L-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia and reduction of indole metabolites. D-cysteine treatment increased tryptophan metabolites in the kynurenine pathway, decreased those in the serotonin pathway and enriched the genera Bacteroides and Odoribacter abundance. CONCLUSION In summary, these results suggest that L- and D-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites and restorating NO and RAS.

Dietary Supplementation with Cysteine during Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulfide and Microbiota-Derived Tryptophan Metabolites.

Maternal chronic kidney disease (CKD) is linked to offspring hypertension. The gut microbiome and its tryptophan metabolites, nitric oxide (NO), and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulfide (H2S) has shown an anti-hypertensive effect. Our objective was to test whether l- or d-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and to explore the protective mechanisms. CKD was induced in pregnant Sprague Dawley rats by a 0.5% adenine diet for 3 weeks. l- or d-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8 per group). Maternal CKD-induced hypertension was similarly prevented by l- or d-cysteine supplementation. The protective effects of l- and d-cysteine are related to reducing oxidative stress, rebalancing the RAS, and reshaping the gut microbiome. l-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia, and the reduction of several indole metabolites. d-cysteine treatment increased kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid in the kynurenine pathway, decreased 5-hydroxytryptophan and serotonin in the serotonin pathway, and enriched genera Bacteroides and Odoribacter abundance. In summary, these results suggest that l- and d-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites, and the restoration of NO and RAS.

Novel Role of Gestational Hydralazine in Limiting Maternal and Dietary Obesity-Related Chronic Kidney Disease.

BackgroundMaternal obesity is a risk factor for chronic kidney disease (CKD) in offspring, underpinning the theory of the developmental origins of health and disease. DNA methylation has been implicated in the programming of adult chronic disease by maternal obesity, therefore, DNA demethylating agents may mitigate offspring risk of disease. In rodent models, low-dose hydralazine has previously been shown to reduce renal fibrosis via DNA demethylation. We used mouse models of maternal obesity and offspring obesity to determine whether administration of low-dose hydralazine during gestation can prevent fetal programming of CKD in offspring.MethodsFemale C57BL/6 mice received high fat diet (HFD) or chow prior to mating, during gestation and lactation. During gestation, dams received subcutaneous hydralazine (5 mg/kg) or saline thrice-weekly. Male offspring weaned to HFD or chow, which continued until endpoint at 32 weeks. Biometric and metabolic parameters, renal global DNA methylation, renal functional and structural changes, and renal markers of fibrosis, inflammation and oxidative stress were assessed at endpoint.ResultsOffspring exposed to maternal obesity or diet-induced obesity had significantly increased renal global DNA methylation, together with other adverse renal effects including albuminuria, glomerulosclerosis, renal fibrosis, and oxidative stress. Offspring exposed to gestational hydralazine had significantly reduced renal global DNA methylation. In obese offspring of obese mothers, gestational hydralazine significantly decreased albuminuria, glomerulosclerosis, and serum creatinine. Obese offspring of hydralazine-treated lean mothers displayed reduced markers of renal fibrosis and oxidative stress.ConclusionGestational hydralazine decreased renal global DNA methylation and exerted renoprotective effects in offspring. This supports a potential therapeutic effect of hydralazine in preventing maternal obesity or dietary obesity-related CKD, through an epigenetic mechanism.

Risk of chronic kidney disease in women with a history of preterm delivery: Tehran Lipid and Glucose Study.

Preterm delivery (PTD) may predict the risk of long-term maternal complications. Little is known about the association between preterm delivery and maternal risk of chronic kidney disease (CKD).This study aimed to explore whether a history of preterm deliveryis associated with the risk of maternal CKD. In this population-based cohort study within the framework of the Tehran Lipid and Glucose Study (TLGS), a total of 3035 women with at least one delivery met our eligibility criteria. A time-dependent Cox proportional-hazards regression model was used to measure the hazard ratios (HRs) and 95% confidence intervals (CIs) for evaluating the association between history of preterm delivery and risk of CKD, adjusted for smoking, parity, age at first delivery, body mass index, educational level, preeclampsia, and gestational diabetes mellitus. A total of 212 women with a history of at least onepreterm delivery and 2823 women with term delivery were included. The median (interquartile range) follow-up in the preterm and term delivery groups was 16 (13.0-17.0) and 16 (14.0-17.0) years, respectively. The results of multivariate Cox regression model, adjusted for confounders, showed that the risk of CKD significantly increased by 46% in women with a history of preterm delivery. Moreover, according to the time-dependent Cox regression analysis, the risk of CKD in women with a history of preterm deliverywas 2.68 (95% CI 1.02, 7.05, P = 0.04) fold higher than among those with no history of preterm delivery. Pregnancy if complicated by preterm delivery, may increase the risk of future maternal morbidities. Our findings suggestthat a history of preterm deliverywas associated with an increased maternal risk of CKD in the long term. Further longitudinal studies are needed to confirm our findings.

An observational claims data analysis on the risk of maternal chronic kidney disease after preterm delivery and preeclampsia

Women with complications of pregnancy such as preeclampsia and preterm birth are at risk for adverse long-term outcomes, including an increased future risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD). This observational cohort study aimed to examine the risk of CKD after preterm delivery and preeclampsia in a large obstetric cohort in Germany, taking into account preexisting comorbidities, potential confounders, and the severity of CKD. Statutory claims data of the AOK Baden-Wuerttemberg were used to identify women with singleton live births between 2010 and 2017. Women with preexisting conditions including CKD, ESKD, and kidney replacement therapy (KRT) were excluded. Preterm delivery (< 37 gestational weeks) was the main exposure of interest; preeclampsia was investigated as secondary exposure. The main outcome was a newly recorded diagnosis of CKD in the claims database. Data were analyzed using Cox proportional hazard regression models. The time-dependent occurrence of CKD was analyzed for four strata, i.e., births with (i) neither an exposure of preterm delivery nor an exposure of preeclampsia, (ii) no exposure of preterm delivery but exposure of at least one preeclampsia, (iii) an exposure of at least one preterm delivery but no exposure of preeclampsia, or (iv) joint exposure of preterm delivery and preeclampsia. Risk stratification also included different CKD stages. Adjustments were made for confounding factors, such as maternal age, diabetes, obesity, and dyslipidemia. The cohort consisted of 193,152 women with 257,481 singleton live births. Mean observation time was 5.44 years. In total, there were 16,948 preterm deliveries (6.58%) and 14,448 births with at least one prior diagnosis of preeclampsia (5.61%). With a mean age of 30.51 years, 1,821 women developed any form of CKD. Compared to women with no risk exposure, women with a history of at least one preterm delivery (HR = 1.789) and women with a history of at least one preeclampsia (HR = 1.784) had an increased risk for any subsequent CKD. The highest risk for CKD was found for women with a joint exposure of preterm delivery and preeclampsia (HR = 5.227). These effects were the same in magnitude only for the outcome of mild to moderate CKD, but strongly increased for the outcome of severe CKD (HR = 11.90). Preterm delivery and preeclampsia were identified as independent risk factors for all CKD stages. A joint exposure or preterm birth and preeclampsia was associated with an excessive maternal risk burden for CKD in the first decade after pregnancy. Since consequent follow-up policies have not been defined yet, these results will help guide long-term surveillance for early detection and prevention of kidney disease, especially for women affected by both conditions.

MO489GESTATIONAL DIABETES AND THE LONG-TERM RISK OF MATERNAL KIDNEY DISEASE: A SWEDISH NATIONAL COHORT STUDY

Abstract Background and Aims Gestational diabetes (GDM) is increasingly common worldwide. GDM is associated with increased risk of type 2 diabetes (T2DM) and cardiovascular disease in women. It is uncertain whether GDM is independently associated with long-term risk of maternal kidney disease. We aimed to examine the association between GDM and maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD) and to determine whether this depends on progression to overt T2DM. Method A nationwide retrospective cohort study was designed using data from the Swedish national registers. Women were included if their first delivery occurred between 1 January 1987 and 31 December 2012. Previous GDM was the main exposure variable, and this was stratified according to whether women developed T2DM after pregnancy. We estimated the risk of CKD, ESKD and different CKD subtypes (tubulointerstitial, glomerular, hypertensive, diabetic, other/non-specific). Cox-proportional hazard regression models were used with time-dependent covariates. We adjusted for a wide range of confounders including maternal age, country of origin, maternal education, parity, antenatal BMI, gestational weight gain, smoking during pregnancy and preeclampsia. Results There were 1,121,633 women included, of whom 15,595 (1.4%) had a diagnosis of GDM. Overall, GDM-diagnosed women were at increased risk of CKD (aHR 1.81, 95% CI 1.54-2.14) and ESKD (aHR 4.52, 95% CI 2.75-7.44). Associations were strongest for diabetic CKD (aHR 8.81, 95% CI 6.36-12.19), hypertensive CKD (aHR 2.46, 95% CI 1.06-5.69), and glomerular CKD (aHR 1.86, 95% CI 1.37-2.51). However, these associations were largely explained by progression to post-pregnancy T2DM. Among women who had GDM + subsequent T2DM, strong associations were observed with CKD (aHR 21.70, 95% CI 17.17-27.42) and ESKD (aHR 112.37, 95% CI 61.22-206.38). By contrast, women who only experienced GDM (and no future T2DM) were not at significantly higher risk of CKD (aHR 1.11, 95% CI 0.89-1.38) or ESKD (aHR 1.58, 95% CI 0.70-3.60). Conclusion Women who experience GDM are at increased risk of CKD and ESKD if they develop T2DM. However, GDM-diagnosed women who do not develop overt T2DM in later life have a similar risk of CKD/ESKD to those with uncomplicated pregnancies.

Pregnancy outcomes in women with chronic kidney disease and chronic hypertension: a National cohort study

Maternal chronic kidney disease and chronic hypertension have been linked with adverse pregnancy outcomes. We aimed to examine the association between these conditions and adverse pregnancy outcomes over the last 3 decades. We conducted this national cohort study to assess the association between maternal chronic disease (CH, CKD or both conditions) and adverse pregnancy outcomes with an emphasis on the effect of parity, maternal age, and BMI on these associations over the last three decades. We further investigated whether different subtypes of CKD had differing effects. We used data from the Swedish Medical Birth Register, including 2,788,490 singleton births between 1982 and 2012. Women with chronic kidney disease and chronic hypertension were identified from the Medical Birth Register and National Patient Register. Logistic regression models were performed to assess the associations between maternal chronic disease (chronic hypertension, chronic kidney disease, or both conditions) and pregnancy outcomes, including preeclampsia, in-labor and prelabor cesarean delivery, preterm birth, small for gestational age, and stillbirth. During the 30-year study period, 22,397 babies (0.8%) were born to women with chronic kidney disease, 13,279 (0.48%) to women with chronic hypertension and 1079 (0.04%) to women with both conditions. Associations with chronic hypertension were strongest for preeclampsia (adjusted odds ratio, 4.57; 95% confidence interval, 4.33-4.84) and stillbirth (adjusted odds ratio, 1.65; 95% confidence interval, 1.35-2.03) and weakest for spontaneous preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.96-1.20). The effect of chronic kidney disease varied from (adjusted odds ratio, 2.05; 95% confidence interval, 1.92-2.19) for indicated preterm birth to no effect for stillbirth (adjusted odds ratio, 1.16; 95% confidence interval, 0.95-1.43). Women with both conditions had the strongest associations for in-labor cesarean delivery (adjusted odds ratio, 1.86; 95% confidence interval, 1.49-2.32), prelabor cesarean delivery (adjusted odds ratio, 2.68; 95% confidence interval, 2.18-3.28), indicated preterm birth (adjusted odds ratio, 9.09; 95% confidence interval, 7.61-10.7), and small for gestational age (adjusted odds ratio, 4.52; 95% confidence interval, 3.68-5.57). The results remained constant over the last 3 decades. Stratified analyses of the associations by parity, maternal age, and body mass index showed that adverse outcomes remained independently higher in women with these conditions, with worse outcomes in multiparous women. All chronic kidney disease subtypes were associated with higher odds of preeclampsia, in-labor cesarean delivery, and medically indicated preterm birth. Different subtypes of chronic kidney disease had differing risks; strongest associations of preeclampsia (adjusted odds ratio, 3.98; 95% confidence interval, 2.98-5.31) and stillbirth (adjusted odds ratio, 2.73; 95% confidence interval, 1.13-6.59) were observed in women with congenital kidney disease, whereas women with diabetic nephropathy had the most pronounced increase odds of in-labor cesarean delivery (adjusted odds ratio, 3.54; 95% confidence interval, 2.06-6.09), prelabor cesarean delivery (adjusted odds ratio, 7.50; 95% confidence interval, 4.74-11.9), and small for gestational age (adjusted odds ratio, 4.50; 95% confidence interval, 2.92-6.94). In addition, women with renovascular disease had the highest increased risk of preterm birth in both spontaneous preterm birth (adjusted odds ratio, 3.01; 95% confidence interval, 1.57-5.76) and indicated preterm birth (adjusted odds ratio, 8.09; 95% confidence interval, 5.73-11.4). Women with chronic hypertension, chronic kidney disease, or both conditions are at an increased risk of adverse pregnancy outcomes which were independent of maternal age, body mass index, and parity. Multidisciplinary management should be provided with intensive clinical follow-up to support these women during pregnancy, particularly multiparous women. Further research is needed to evaluate the effect of disease severity on adverse pregnancy outcomes.

Macrosomia is a risk factor for incident maternal chronic kidney disease

BackgroundGestational diabetes mellitus (GDM) and macrosomia are associated with several adverse outcomes including diabetes mellitus and cardiovascular diseases, however, the relationship between GDM/macrosomia with incident chronic kidney disease (CKD) is a matter of debate. The purpose of this study was to examine the association between the history of macrosomia with or without GDM and incident maternal CKD.MethodsThe study population includes 2669 women aged 18–50 years without known diabetes mellitus and CKD from participants of the Tehran Lipid and Glucose Study. The study population was categorized into 3 groups; group 1: GDM/macrosomia and without diabetes mellitus (n = 204), group 2: newly diagnosed incident diabetes mellitus (NDM) in the presence or abcence of GDM/Macrosomia (n = 113), and, group 3: the reference group including women without prior history of GDM/macrosomia and free of NDM (n = 2352). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Multivariable Cox proportional hazard regression adjusted for baseline values of age, body mass index, waist circumference, parity numbers, smoking, educational level, gestational hypertension, eGFR, systolic and diastolic blood pressures (SBP and DBP, respectively), anti-hypertensive medication, and family history of diabetes mellitus was applied for data analyses.ResultsDuring a median follow-up of 11.9 years, 613 incident CKD cases were identified. The multivariable hazard ratio (HR) and 95% confidence interval (CI) on GDM/macrosomia group was [1.32 (1.02–1.72)]; the risk was more prominent among non-hypertensive women [1.41 (1.07–1.85); P for interaction: 0.046]. Moreover, the history of macrosomia alone also showed a significant risk [1.36 (1.04–1.78)]; however, history of GDM alone did not have a significant risk [0.92 (0.34–2.46)]. Age, current smoking, eGFR, and SBP remained as independent risk factors for incident CKD.ConclusionsA history of GDM/macrosomia or macrosomia alone, independent of subsequent diabetes mellitus was associated with significant risk for incident maternal CKD. Pregnancy may provide a unique situation to identify high-risk women at risk for CKD that could benefit from regular monitoring of kidney function and providing risk modifying strategies.

Maternal and Fetal Outcomes of Pregnancy in Nephrotic Syndrome Due to Primary Glomerulonephritis.

Chronic kidney disease (CKD) affects 3% of pregnancies, impacting on maternal and fetal outcomes, and at the same time, a recurrent question in nephrology regards gestation impact on kidney function. Observational studies stated that CKD stage, pre-existent hypertension, and proteinuria are the main predictors of possible complications, such as maternal CKD progression, maternal or fetal death, prematurity, small for gestational age (SGA) newborn, or admission to the neonatal intensive care unit. In this regard, given the prominence of proteinuria among other risk factors, we focused on primary nephrotic syndrome in pregnancy, which accounts for 0.028% of cases, and its impact on materno-fetal outcomes and kidney survival. Data extracted from literature are scattered because of the small cohorts investigated in each trial. However, they showed different outcomes for each glomerular disease, with membranous nephropathy (MN) having a better maternal and fetal prognosis than focal and segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), or minimal change disease (MCD). Nephrotic syndrome does not have to discourage women to undertake a pregnancy, but the correct management may include a specific evaluation of risk factors and follow-up for adverse materno-fetal events and/or maternal kidney disease progression.

Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites.

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.

Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites.

Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.

Preeclampsia and the risk of chronic kidney disease: a national registry-based cohort study

Abstract Background Preeclampsia is associated with increased risk of future cardiovascular disease, but evidence for associations with chronic kidney disease (CKD) has been inconsistent to date. We aimed to measure associations between preeclampsia and long-term CKD in a population-based sample of parous women, and to identify whether the risk differs by CKD subtype. Methods Using data from the Swedish Medical Birth Register, singleton live births from 1973-2012 were identified and linked to data from the Swedish Renal Register and National Patient Register (up to 2013). Preeclampsia was the main exposure of interest and was treated as a time-dependent variable. The primary outcome was maternal CKD, and this was classified into 5 subtypes: hypertensive, diabetic, glomerular/proteinuric, tubulo-interstitial, other/non-specific CKD. Cox proportional hazard regression models were used for analysis. Women with pre-pregnancy comorbidities were excluded. Results The dataset included 1,924,591 unique women who had 3,726,819 singleton pregnancies. The median follow-up was 20.7 (interquartile range 9.9-30.0) years. Overall, 90,964 women (4.7%) experienced preeclampsia and 18,146 (0.9%) developed CKD. Women who had preeclampsia had higher risk of developing any CKD during follow-up (aHR 1.88, 95% CI 1.79-1.98). The risk differed by CKD subtype, and was higher for hypertensive CKD (aHR 3.76, aHR 3.09-4.57), diabetic CKD (aHR 3.45, 95% CI 2.83-4.21) and glomerular/proteinuric CKD (aHR 2.08, 95% CI 1.90-2.29). Women who had preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity were also at greater risk of any CKD. Conclusions Women with a history of preeclampsia are at increased risk of long-term CKD. The risk is most marked for hypertensive CKD, diabetic CKD, and glomerular/proteinuric CKD. The absolute risk of CKD related to preeclampsia is substantial, and these women may warrant systematic renal monitoring in the years following delivery. Key messages Preeclampsia is an independent predictor of long-term risk of chronic kidney disease in otherwise healthy parous women. Women with a history of preeclampsia may warrant systematic renal monitoring through additional blood pressure, blood glucose, and proteinuria checks.

Hypertensive disorders of pregnancy and the risk of chronic kidney disease: ASwedish registry-based cohort study.

Hypertensive disorders of pregnancy (HDP) (preeclampsia, gestational hypertension) are associated with an increased risk of end-stage kidney disease (ESKD). Evidence for associations between HDP and chronic kidney disease (CKD) is more limited and inconsistent. The underlying causes of CKD are wide-ranging, and HDP may have differential associations with various aetiologies of CKD. We aimed to measure associations between HDP and maternal CKD in women who have had at least one live birth and to identify whether the risk differs by CKD aetiology. Using data from the Swedish Medical Birth Register (MBR), singleton live births from 1973 to 2012 were identified and linked to data from the Swedish Renal Register (SRR) and National Patient Register (NPR; up to 2013). Preeclampsia was the main exposure of interest and was treated as a time-dependent variable. Gestational hypertension was also investigated as a secondary exposure. The primary outcome was maternal CKD, and this was classified into 5 subtypes: hypertensive, diabetic, glomerular/proteinuric, tubulointerstitial, and other/nonspecific CKD. Cox proportional hazard regression models were used, adjusting for maternal age, country of origin, education level, antenatal BMI, smoking during pregnancy, gestational diabetes, and parity. Women with pre-pregnancy comorbidities were excluded. The final sample consisted of 1,924,409 women who had 3,726,554 singleton live births. The mean (±SD) age of women at first delivery was 27.0 (±5.1) years. Median follow-up was 20.7 (interquartile range [IQR] 9.9-30.0) years. A total of 90,917 women (4.7%) were diagnosed with preeclampsia, 43,964 (2.3%) had gestational hypertension, and 18,477 (0.9%) developed CKD. Preeclampsia was associated with a higher risk of developing CKD during follow-up (adjusted hazard ratio [aHR] 1.92, 95% CI 1.83-2.03, p < 0.001). This risk differed by CKD subtype and was higher for hypertensive CKD (aHR 3.72, 95% CI 3.05-4.53, p < 0.001), diabetic CKD (aHR 3.94, 95% CI 3.38-4.60, p < 0.001), and glomerular/proteinuric CKD (aHR 2.06, 95% CI 1.88-2.26, p < 0.001). More modest associations were observed between preeclampsia and tubulointerstitial CKD (aHR 1.44, 95% CI 1.24-1.68, p < 0.001) or other/nonspecific CKD (aHR 1.51, 95% CI 1.38-1.65, p < 0.001). The risk of CKD was increased after preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity. Women who had gestational hypertension also had increased risk of developing CKD (aHR 1.49, 95% CI 1.38-1.61, p < 0.001). This association was strongest for hypertensive CKD (aHR 3.13, 95% CI 2.47-3.97, p < 0.001). Limitations of the study are the possibility that cases of CKD were underdiagnosed in the national registers, and some women may have been too young to have developed symptomatic CKD despite the long follow-up time. Underreporting of postpartum hypertension is also possible. In this study, we found that HDP are associated with increased risk of maternal CKD, particularly hypertensive or diabetic forms of CKD. The risk is higher after preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity. Women who experience HDP may benefit from future systematic renal monitoring.