State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies.

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

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.

Decreased Risk of Preeclampsia in Women with Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy.

BACKGROUND: Evidence suggests that upregulation of tumor necrosis factor-alpha (TNF-α) plays a role in immune dysregulation in both preeclampsia and inflammatory bowel disease (IBD). AIMS: We aimed to investigate whether anti-TNF therapy during pregnancy decreases the risk of preeclampsia in women with IBD. METHODS: The study population included women with IBD and pregnancies who were followed at a tertiary care center from 2007 to 2021. Cases of preeclampsia were compared with controls with a normotensive pregnancy. Data on patient demographics, disease type and activity, pregnancy complications, and additional risk factors for preeclampsia were collected. The association between anti-TNF therapy and preeclampsia was analyzed using univariate analysis and multivariate logistic regression. RESULTS: Women with preeclampsia were more likely to have a preterm delivery (44% vs. 12%, p < 0.001). More women without preeclampsia were exposed to anti-TNF therapy during pregnancy than women with preeclampsia (55% vs. 30%, p = 0.029). The majority of women (32/44) on anti-TNF therapy, either adalimumab or infliximab, continued to have some degree of exposure during the third trimester. Though not significant, multivariate analysis showed a trend towards a protective effect of anti-TNF therapy against developing preeclampsia if exposed during the third trimester (OR 0.39; 95% CI 0.14-1.12, p = 0.08). CONCLUSIONS: In this study, anti-TNF therapy exposure was higher in IBD patients who did not develop preeclampsia than in those who did. While not significant, there was a trend towards a protective effect of anti-TNF therapy against preeclampsia if exposed during the third trimester.

Pharmacist-provider collaborative visits after hospital discharge in a comprehensive acute kidney injury survivor model.

BACKGROUND: Postdischarge follow-up in primary care is an opportunity for pharmacists to re-evaluate medication use in acute kidney injury (AKI) survivors. Of the emerging AKI survivor care models described in literature, only one involved a pharmacist with limited detail about the direct impact. OBJECTIVE: This study aimed to describe pharmacist contributions to a comprehensive postdischarge AKI survivorship program in primary care (the AKI in Care Transitions [ACT] program). METHODS: The ACT program was piloted from May to December of 2021 at Mayo Clinic as a bundled care strategy for patients who survived an episode of AKI and were discharged home without the need for hemodialysis. Patients received education and care coordination from nurses before discharge and later completed postdischarge laboratory assessment and clinician follow-up in primary care. During the follow-up encounter, patients completed a 30-minute comprehensive medication management visit with a pharmacist focusing on AKI survivorship considerations. Medication therapy recommendations were communicated to a collaborating primary care provider (PCP) before a separate 30-minute visit with the patient. PCPs had access to clinical decision support with evidence-based post-AKI care recommendations. Medication-related issues were summarized descriptively. RESULTS: Pharmacists made 28 medication therapy recommendations (median 3 per patient, interquartile range 2-3) and identified 14 medication discrepancies for the 11 patients who completed the pilot program, and 86% of the medication therapy recommendations were acted on by the PCP within 7 days. Six recommendations were made to initiate renoprotective medications, and 5 were acted on (83%). CONCLUSION: During the pilot phase of a multifaceted transitional care program for AKI survivors, pharmacists' successfully identified and addressed multiple medication therapy problems, including for renally active drugs. These results demonstrate the potential for pharmacist-provider collaborative visits in primary care to improve safe and effective medication use in AKI survivors.

The Effect of Gender-Affirming Hormone Therapy on Serum Creatinine in Transgender Individuals.

OBJECTIVE: To describe the changes in serum creatinine (Cr) levels after the initiation of gender-affirming hormone therapy (GAHT) in transgender individuals to better understand the expected changes and interpretation of laboratory values in this population. METHODS: A retrospective chart review of all adult transgender patients initiated on GAHT at Mayo Clinic from January 2011 to October 2019 was completed. Laboratory values were obtained prior to initiating GAHT and at 3, 6, and 12 months after initiating GAHT. Baseline Cr values were compared with Cr values at 3, 6, and 12 months after initiating GAHT in transgender men (TM) on testosterone and transgender women (TW) on estradiol and antiandrogens. RESULTS: A total of 84 TW (median age of 30 years) and 24 TM (median age of 23 years) were included for analysis. Following a matched pair analysis of TW, Cr values were found to be significantly decreased by -0.03 at 3 months (P = .04), -0.10 at 6 months (P < .01), and -0.07 at 12 months (P < .01) compared with baseline values. Following a matched pair analysis of TM, Cr values were found to be significantly increased, on average, by 0.14 at 3 months (P = .04), 0.21 at 6 months (P = .016), and 0.15 at 12 months (P = .003) compared with baseline values. CONCLUSION: In TW and TM, a change in Cr level was seen as early as 3 months toward their affirmed gender after initiating GAHT. Clinicians can use Cr levels established at 6 months as new baseline values, as these changes continue to persist up to 12 months.

Risk of Symptomatic Kidney Stones During and After Pregnancy.

RATIONALE & OBJECTIVE: There are several well-known anatomical and physiological changes during pregnancy that could contribute to kidney stone formation, but evidence that they increase the risk of kidney stones during pregnancy is lacking. We determined whether there was an increased risk of a first-time symptomatic kidney stone during and after pregnancy. STUDY DESIGN: A population-based matched case-control study. SETTING & PARTICIPANTS: 945 female first-time symptomatic kidney stone formers aged 15-45 years and 1,890 age-matched female controls in Olmsted County, MN, from 1984-2012. The index date was the date of onset of a symptomatic kidney stone for both the case and her matched controls. EXPOSURE: The primary exposure was pregnancy with assessment for variation in risk across different time intervals before, during, and after pregnancy. Medical records were manually reviewed to determine the conception and delivery dates for pregnancies. OUTCOME: Medical record-validated first-time symptomatic kidney stone. ANALYTICAL APPROACH: Conditional and unconditional multivariable logistic regression analysis. RESULTS: Compared with nonpregnant women, the odds of a symptomatic kidney stone forming in women was similar in the first trimester (OR, 0.92; P=0.8), began to increase during the second trimester (OR, 2.00; P=0.007), further increased during the third trimester (OR, 2.69; P=0.001), peaked at 0 to 3 months after delivery (OR, 3.53; P<0.001), and returned to baseline by 1year after delivery. These associations persisted after adjustment for age and race or for diabetes mellitus, hypertension, and obesity. These results did not significantly differ by age, race, time period, or number of prior pregnancies. Having a prior pregnancy (delivery date>1year ago) was also associated with a first-time symptomatic kidney stone (OR, 1.27; P=0.01). LIMITATIONS: Observational study design in a predominantly White population. The exact timing of stone formation cannot be determined. CONCLUSIONS: Pregnancy increases the risk of a first-time symptomatic kidney stone. This risk peaks close to delivery and then improves by 1 year after delivery, though a modest risk of a kidney stone still exists beyond 1 year after delivery.

Peritoneal-mediastinal communication complication in peritoneal dialysis.

Peritoneal-mediastinal communication is a rare complication of peritoneal dialysis (PD). We report the first case of peritoneal-mediastinal communication complication in a 36-year-old Caucasian man on continuous cycler peritoneal dialysis (CCPD) after undergoing cardiac surgery. He developed end-stage kidney disease (ESKD) due to calcineurin inhibitor nephrotoxicity and BK virus nephropathy in the setting of prior heart transplantation. He was initially started on intermittent hemodialysis (iHD) and was switched to CCPD 1 year later. He presented with increased drainage from his sternal incision site and reduced ultrafiltration. A contrast-enhanced chest computed tomography scan revealed an anterior chest wall subcutaneous fluid collection. He was found to have a peritoneal-mediastinal communication intraoperatively. He was successfully managed with "low-volume" PD by using reduced fill volumes for all his exchanges and did not require transition to iHD. He also had no vascular access options because of multiple prior thromboses, which would have made transitioning to iHD not feasible. This case further highlights the complex management of an ESKD patient who cannot do iHD and only do low-volume PD because of a surgical complication and the need for a multidisciplinary approach to ensure appropriate patient care.

Comparison of hospitalization outcomes for delivery and resource utilization between pregnant women with kidney transplants and chronic kidney disease in the United States.

BACKGROUND: This study aimed to assess outcomes of delivery hospitalizations, including acute kidney injury (AKI), obstetric and foetal events and resource utilization among pregnant women with kidney transplants compared with pregnant women with no known kidney disease and those with chronic kidney disease (CKD) Stages 3-5. METHOD: Hospitalizations for delivery in the US were identified using the enhanced delivery identification method in the National Inpatient Sample dataset from the years 2009 to 2014. Diagnoses of CKD Stages 3-5, kidney transplantation, along with obstetric events, delivery methods and foetal events were identified using ICD-9-CM diagnosis and procedure codes. Patients with no known kidney disease group were identified by excluding any diagnoses of CKD, end stage kidney disease, and kidney transplant. Multivariable logistic regression accounting for the survey weights and matched regression was conducted to investigate the risk of maternal and foetal complications in women with kidney transplants, compared with women with no kidney transplants and no known kidney disease, and to women with CKD Stages 3-5. RESULT: A total of 5, 408, 215 hospitalizations resulting in deliveries were identified from 2009 to 2014, including 405 women with CKD Stages 3-5, 295 women with functioning kidney transplants, and 5, 405, 499 women with no known kidney disease. Compared with pregnant women with no known kidney disease, pregnant kidney transplant recipients were at higher odds of hypertensive disorders of pregnancy (OR = 3.11, 95% CI [2.26, 4.28]), preeclampsia/eclampsia/HELLP syndrome (OR = 3.42, 95% CI [2.54, 4.60]), preterm delivery (OR = 2.46, 95% CI [1.75, 3.45]), foetal growth restriction (OR = 1.74, 95% CI [1.01, 3.00]) and AKI (OR = 10.46, 95% CI [5.33, 20.56]). There were no significant differences in rates of gestational diabetes or caesarean section. Pregnant women with kidney transplants had 1.30-times longer lengths of stay and 1.28-times higher costs of hospitalization. However, pregnant women with CKD Stages 3-5 were at higher odds of AKI (OR = 5.29, 95% CI [2.41, 11.59]), preeclampsia/eclampsia/HELLP syndrome (OR = 1.72, 95% CI [1.07, 2.76]) and foetal deaths (OR = 3.20, 95% CI [1.06, 10.24]), and had 1.28-times longer hospital stays and 1.37-times higher costs of hospitalization compared with pregnant women with kidney transplant. CONCLUSION: Pregnant women with kidney transplant were more likely to experience adverse events during delivery and had longer lengths of stay and higher total charges when compared with women with no known kidney disease. However, pregnant women with moderate to severe CKD were more likely to experience serious complications than kidney transplant recipients.

Subtyping Hyperchloremia among Hospitalized Patients by Machine Learning Consensus Clustering.

Background and Objectives: Despite the association between hyperchloremia and adverse outcomes, mortality risks among patients with hyperchloremia have not consistently been observed among all studies with different patient populations with hyperchloremia. The objective of this study was to characterize hyperchloremic patients at hospital admission into clusters using an unsupervised machine learning approach and to evaluate the mortality risk among these distinct clusters. Materials and Methods: We performed consensus cluster analysis based on demographic information, principal diagnoses, comorbidities, and laboratory data among 11,394 hospitalized adult patients with admission serum chloride of >108 mEq/L. We calculated the standardized mean difference of each variable to identify each cluster's key features. We assessed the association of each hyperchloremia cluster with hospital and one-year mortality. Results: There were three distinct clusters of patients with admission hyperchloremia: 3237 (28%), 4059 (36%), and 4098 (36%) patients in clusters 1 through 3, respectively. Cluster 1 was characterized by higher serum chloride but lower serum sodium, bicarbonate, hemoglobin, and albumin. Cluster 2 was characterized by younger age, lower comorbidity score, lower serum chloride, and higher estimated glomerular filtration (eGFR), hemoglobin, and albumin. Cluster 3 was characterized by older age, higher comorbidity score, higher serum sodium, potassium, and lower eGFR. Compared with cluster 2, odds ratios for hospital mortality were 3.60 (95% CI 2.33-5.56) for cluster 1, and 4.83 (95% CI 3.21-7.28) for cluster 3, whereas hazard ratios for one-year mortality were 4.49 (95% CI 3.53-5.70) for cluster 1 and 6.96 (95% CI 5.56-8.72) for cluster 3. Conclusions: Our cluster analysis identified three clinically distinct phenotypes with differing mortality risks in hospitalized patients with admission hyperchloremia.

Preeclampsia and Kidney Disease: Deciphering Cause and Effect.

PURPOSE OF REVIEW: Preeclampsia and chronic kidney disease have a complex, bidirectional relationship. Women with kidney disease, with even mild reductions in glomerular filtrate rate, have an increased risk of developing preeclampsia. Preeclampsia, in turn, has been implicated in the subsequent development of albuminuria, chronic kidney disease, and end-stage kidney disease. We will discuss observational evidence and mechanisms linking the two disease processes. RECENT FINDINGS: Preeclampsia is characterized by an imbalance in angiogenic factors that causes systemic endothelial dysfunction. Chronic kidney disease may predispose to the development of preeclampsia due to comorbid conditions, such as hypertension, but is also associated with impaired glycocalyx integrity and alterations in the complement and renin-angiotensin-aldosterone systems. Preeclampsia may lead to kidney disease by causing acute kidney injury, endothelial damage, and podocyte loss. Preeclampsia may be an important sex-specific risk factor for chronic kidney disease. Understanding how chronic kidney disease increases the risk of preeclampsia from a mechanistic standpoint may open the door to future biomarkers and therapeutics for all women.

Association of Partial versus Radical Nephrectomy with Subsequent Hypertension Risk Following Renal Tumor Resection.

PURPOSE: We investigated the risks of new onset and worsened hypertension after radical vs partial nephrectomy. MATERIALS AND METHODS: Using a national administrative database of privately and Medicare insured patients we performed a retrospective cohort study of 9,207 and 4,686 patients who underwent radical and partial nephrectomy, respectively, for a renal mass between January 1, 2007 and December 31, 2016. One-to-one propensity score matching was done to balance the surgical groups based on patient demographics, baseline comorbidities, current medications and surgery year. Primary outcomes included new onset hypertension among patients with no history of hypertension and worsened hypertension among patients with baseline hypertension. We performed subgroup analyses stratified by patient age (75 or greater vs less than 75 years) and the presence of baseline kidney disease. Incidence rates and Cox proportional hazards models were used to compare outcomes in matched cohorts. RESULTS: Among 3,106 propensity matched patients without preexisting hypertension radical nephrectomy was associated with a higher risk of new onset hypertension compared to partial nephrectomy (HR 1.40, 95% CI 1.22-1.60, p <0.001). Similarly among 6,250 propensity matched patients with hypertension prior to surgery radical nephrectomy was associated with a higher risk of worsening baseline hypertension (HR 1.18, 95% CI 1.10-1.26, p <0.001). Subgroup analyses were consistent with the main study findings of worsened hypertension (p for interaction ≥0.05). CONCLUSIONS: Radical nephrectomy was associated with a higher risk of new onset and worsened hypertension compared to partial nephrectomy, including among elderly patients and individuals with normal kidney function. Given prior noted associations between hypertension and noncancer related morbidity, our results further encourage the preferential use of partial nephrectomy to manage localized renal masses when technically feasible.

Renal Disorders in Pregnancy: Core Curriculum 2019.

As the incidence of chronic kidney disease increases and women pursue pregnancy at more advanced ages, the management of kidney disease in pregnancy has become increasingly relevant to the practicing nephrologist. Women with kidney disorders face several challenges in pregnancy due to increased physiologic demands on the kidney and risk for disease progression, the potential teratogenicity of medications, and the increased risk for complications such as preeclampsia and preterm delivery. Challenges posed by an underlying disease process in pregnancy, such as autoimmune disease or diabetes mellitus, necessitate an interdisciplinary team to ensure good maternal and fetal outcomes. Rates of acute kidney injury in pregnancy are generally declining worldwide, but remain a significant public health concern in developing countries. Pregnancy may also be the first time that a woman has kidney disease or hypertension diagnosed. An understanding of what constitutes normal physiologic changes in pregnancy is critical in a diagnostic evaluation. In this review, we review physiologic changes in pregnancy, causes and management of acute kidney injury in pregnancy, hypertensive disorders of pregnancy, and how to care for women with chronic kidney disease of various causes, including the use of antihypertensives and immunosuppressants.

Spot urine protein measurements in normotensive pregnancies, pregnancies with isolated proteinuria and preeclampsia.

We performed a prospective, longitudinal study of pregnant women presenting to their first obstetrics visits to characterize the changes in spot urine protein-to-creatinine (UPCR) and albumin-to-creatinine ratios (UACR) in normotensive pregnancies, as well as identify clinical characteristics associated with isolated proteinuria and preeclampsia. We measured spot urinary albumin, protein, and creatinine at the first prenatal visit, end of the second trimester, and at delivery. In the normotensive pregnancies (n = 142), we found that from the beginning of pregnancy to delivery, UACR increased by a median [interquartile range (IQR)] of 14.7 mg/g Cr (3.74-51.8) and UPCR by 60 mg/g Cr (30-130) (P < 0.001 for both changes). Isolated proteinuria (defined as UPCR > 300 mg/g Cr in the absence of hypertension) was identified in 19/142 (13.4%) normotensive pregnancies. Increases in systolic and diastolic blood pressure from early pregnancy to delivery and increases in UACR from early to midpregnancy were associated with isolated proteinuria at delivery. Twelve women developed preeclampsia. Nulliparity, early, and midpregnancy diastolic blood pressures were strongly associated with the development of preeclampsia, but early changes in UACR were not. In conclusion, women who develop isolated proteinuria at delivery have a larger increase in blood pressure than women without proteinuria and have a "microalbuminuric" phase earlier in gestation, unlike women who develop preeclampsia. These findings suggest a different mechanism of urine protein excretion in women with isolated proteinuria as compared with women with preeclampsia, where proteinuria has a more abrupt onset.

Preeclampsia and ESRD: The Role of Shared Risk Factors.

BACKGROUND: Several registry-based studies, using diagnostic codes, have suggested that preeclampsia is a risk factor for end-stage renal disease (ESRD). However, because the 2 diseases share risk factors, the true nature of their association remains uncertain. Our goals were to conduct a population-based study to determine the magnitude of the association between preeclampsia and ESRD and evaluate the role of shared risk factors. STUDY DESIGN: Population-based nested case-control study. SETTING & PARTICIPANTS: The US Renal Data System was used to identify women with ESRD from a cohort of 34,581 women who gave birth in 1976 to 2010 in Olmsted County, MN. 44 cases of ESRD were identified and each one was matched to 2 controls based on year of birth (±1 year), age at first pregnancy (±2 years), and parity (±1 or ≥4). PREDICTOR: Preeclamptic pregnancy, confirmed by medical record review. OUTCOME: ESRD. MEASUREMENTS: Prepregnancy serum creatinine and urine protein measurements were recorded. Comorbid conditions existing prior to pregnancy were abstracted from medical records and included kidney disease, obesity, diabetes, and hypertension. RESULTS: There was evidence of kidney disease prior to the first pregnancy in 9 of 44 (21%) cases and 1 of 88 (<1%) controls. Per chart review, 8 of 44 (18%) cases versus 4 of 88 (5%) controls had preeclamptic pregnancies (unadjusted OR, 4.0; 95% CI, 1.21-13.28). Results were similar after independent adjustment for race, education, diabetes, and hypertension prior to pregnancy. However, the association was attenuated and no longer significant after adjustment for obesity (OR, 3.25; 95% CI, 0.93-11.37). LIMITATIONS: The limited number of ESRD cases and missing data for prepregnancy kidney function. CONCLUSIONS: Our findings confirm that there is a sizable association between preeclampsia and ESRD; however, obesity is a previously unexplored confounder. Pre-existing kidney disease was common, but not consistently coded or diagnosed.

Urinary Oxalate Excretion During Pregnancy in Primary Hyperoxaluria Type 1: A Report of 4 Cases.

Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive oxalate production because of specific gene defects. PH1 is the most prevalent type, causing recurrent kidney stone disease and often leading to chronic kidney disease and kidney failure. Our previous study suggested that pregnancy did not adversely affect kidney function in female patients with PH. In this study, we identified 4 PH1 cases with urinary oxalate (UOx) measurements during pregnancy from the Rare Kidney Stone Consortium and Oxalosis and Hyperoxaluria Foundation PH registry to investigate UOx levels during pregnancy in patients with PH1. The PH Registry is approved by the Institutional Review Board of Mayo Clinic (Rochester, MN). All 4 showed a decrease in UOx during pregnancy when compared with before pregnancy and after delivery. These findings contrast with those of the general population, in which the UOx tends to increase during pregnancy because of a simultaneous physiological increase in the glomerular filtration rate. Elucidating the mechanism underlying reduced UOx during pregnancy in PH1 could suggest novel PH therapies. These findings could also affect the clinical management and have implications regarding the safety of withholding novel PH1-directed molecular therapies that currently have uncertain safety profiles during pregnancy. We highlight the need for additional data on urinary changes in patients with PH and other populations while pregnant to clarify changes in UOx throughout pregnancy.