Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies.

BACKGROUND: Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption. METHODS: In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls. RESULTS: Experiments with the knockout mice and in vitro transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA. CONCLUSIONS: Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.

Impact of parathyroidectomy on kidney graft function in post-transplant tertiary hyperparathyroidism: a comparative study.

PURPOSE: Parathyroidectomy to treat tertiary hyperparathyroidism (THPT) is now on a par with calcimimetic treatment. The effects of cinacalcet and parathyroidectomy on kidney transplant function remain controversial. The aim of this study was to evaluate kidney transplant function in THPT patients treated either by parathyroidectomy, cinacalcet, or not treated. METHODS: Between 2009 and 2019, 231 patients with functional grafts presenting THPT, defined either by calcaemia superior to 2.5 mmol/L with elevated PTH level or hypercalcaemia with non-adapted PTH level 1 year after kidney transplantation, were included. Hyperparathyroid patients treated by cinacalcet and parathyroidectomy were matched for age, sex, graft rank, and baseline eGFR with cinacalcet-only and untreated patients. Conditional logistic regression models were used to compare eGFR variations 1 year after parathyroidectomy between operated patients and matched controls. Five-year survivals were compared with the Mantel-Cox test. RESULTS: Eleven patients treated with parathyroidectomy and cinacalcet were matched with 16 patients treated by cinacalcet-only and 29 untreated patients. Demographic characteristics were comparable between groups. Estimated odds ratios for eGFR evolution in operated patients compared with cinacalcet-only and untreated patients were 0.92 [95%CI 0.83-1.02] and 0.99 [0.89-1.10] respectively, indicating no significant impairment of eGFR 1 year after surgery. Five-year allograft survival was not significantly impaired in operated patients. CONCLUSIONS: Parathyroidectomy did not appear to substantially alter or improve graft function 1 year after surgery or 5-year allograft survival. It could be hypothesized that in addition to its known benefits, parathyroidectomy can be safely performed vis-à-vis graft function in tertiary hyperparathyroidism.

Differential localization patterns of claudin 10, 16, and 19 in human, mouse, and rat renal tubular epithelia.

Functional properties of the paracellular pathway depend critically on the set of claudins (CLDN) expressed at the tight junction. Two syndromes are causally linked to loss-of-function mutations of claudins: hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX) syndrome caused by genetic variations in the CLDN10 gene and familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by genetic variations in the CLDN16 or CLDN19 genes. All three genes are expressed in the kidney, particularly in the thick ascending limb (TAL). However, localization of these claudins in humans and rodents remains to be delineated in detail. We studied the segmental and subcellular expression of CLDN10, CLDN16, and CLDN19 in both paraffin-embedded and frozen kidney sections from the adult human, mouse, and rat using immunohistochemistry and immunofluorescence, respectively. Here, CLDN10 was present in a subset of medullary and cortical TAL cells, localizing to basolateral domains and tight junctions in human and rodent kidneys. Weak expression was detected at the tight junction of proximal tubular cells. CLDN16 was primarily expressed in a subset of TAL cells in the cortex and outer stripe of outer medulla, restricted to basolateral domains and tight junctional structures in both human and rodent kidneys. CLDN19 predominantly colocalized with CLDN16 in tight junctions and basolateral domains of the TAL but was also found in basolateral and junctional domains in more distal sites. CLDN10 expression at tight junctions almost never overlapped with that of CLND16 and CLDN19, consistent with distinct junctional pathways with different permeation profiles in both human and rodent kidneys.NEW & NOTEWORTHY This study used immunohistochemistry and immunofluorescence to investigate the distribution of claudin 10, 16, and 19 in the human, mouse, and rat kidney. The findings showed distinct junctional pathways in both human and rodent kidneys, supporting the existence of different permeation profiles in all species investigated.

Impact of Permanent Post-thyroidectomy Hypoparathyroidism on Self-evaluation of Quality of Life and Voice: Results From the National QoL-Hypopara Study.

OBJECTIVE: The aim of this study was to compare the quality of life (mental health) and voice in patients with or without permanent hypoparathyroidism after total thyroidectomy. SUMMARY BACKGROUND DATA: Permanent hypoparathyroidism is an underestimated complication of thyroid surgery owing to suppression of parathormone secretion. Few studies have evaluated the consequences of hypoparathyroidism on quality of life and none has studied its effects on voice. METHODS: The QoL-hypopara study (ClinicalTrial.gov NCT04053647) was a national observational study. Adult thyroidectomized patients were included between January and June 2020. A serum parathormone level <15 pg/mL >6 months after surgery defined permanent hypoparathyroidism. Patients answered the MOS-36-item short-form health (SF-36), the Voice Handicap Index (VHI) surveys, and a list of questions regarding their symptoms. RESULTS: A total of 141 patients were included, 45 with permanent hypoparathyroidism. The median period between thyroid surgery and the questionnaire was 6 (Q1-Q3 4-11) and 4 (4-5) years in hypoparathyroid patients and controls respectively. Hypoparathyroid patients presented a reduced median mental score ratio (SF-36) [0.88 (Q1-Q3 0.63-1.01) vs 1.04 (0.82-1.13), P = 0.003] and a lower voice quality (incidence rate ratio for total VHI 1.83-fold higher, P < 0.001). In multivariable analysis, hypoparathyroidism [-0.17 (95% confidence interval -0.28 to -0.07), P = 0.002], but not age, female sex, thyroid cancer, or abnormal TSH level, was associated with the reduced mental score ratio. Myalgia, joint pain, paresthesia, tetany, anxiety attack, and exhaustion were the most common symptoms among hypoparathyroid patients (>50%). CONCLUSIONS: Hypoparathyroid patients present significantly impaired quality of life, lower voice quality, and frequent symptoms. These results reinforce the importance of preventing this complication.

Early recognition of cardiac surgery-associated acute kidney injury: lack of added value of TIMP2 IGFBP7 over short-term changes in creatinine (an observational pilot study).

BACKGROUND: For the detection of cardiac surgery-associated acute kidney injury (CS-AKI), the performance of urine tissue inhibitor of metalloproteinase 2 insulin-like growth factor-binding protein 7 (TIMP2 IGFBP7) has never been compared with that of very early changes in plasma creatinine (∆pCr). We hypothesized that, in the context of perioperative haemodilution, lack of postoperative decrease in pCr would be of honourable performance for the detection of CS-AKI. We therefore aimed at comparing these biomarkers and their kinetics (primary objective). As secondary objectives, we assessed plasma neutrophil gelatinase-associated lipocalin (pNGAL), cystatin C (pCysC) and urea (pUrea). We also determined the ability of these biomarkers to early discriminate persistent from transient CS-AKI. METHODS: Patients over 75 years-old undergoing aortic valve replacement with cardiopulmonary bypass (CPB) were included in this prospective observational study. Biomarkers were measured before/after CPB and at the sixth postoperative hour (H6). RESULTS: In 65 patients, CS-AKI occurred in 27 (42%). ∆pCr from post-CPB to H6 (∆pCrpostCPB-H6): outperformed TIMP2 IGFBP7 at H6 and its intra- or postoperative changes: area under the receiver operating characteristic curve (AUCROC) of 0.84 [95%CI:0.73-0.92] vs. ≤0.67 [95%CI:0.54-0.78], p ≤ 0.03. The AUCROC of pNGAL, pCysC and pUrea did not exceed 0.72 [95%CI:0.59-0.83]. Indexing biomarkers levels for blood or urine dilution did not improve their performance. Combining TIMP2 IGFBP7 and ∆pCrpostCPB-H6 was of no evident added value over considering ∆pCrpostCPB-H6 alone. For the early recognition of persistent CS-AKI, no biomarker outperformed ∆pCrpostCPB-H6 (AUCROC = 0.69 [95%CI:0.48-0.85]). CONCLUSIONS: In this hypothesis-generating study mostly testing early detection of mild CS-AKI, there was no evident added value of the tested modern biomarkers over early minimal postoperative changes in pCr: despite the common perioperative hemodilution in the setting of cardiac surgery, if pCr failed to decline within the 6 h after CPB, the development of CS-AKI was likely. Confirmatory studies with more severe forms of CS-AKI are required.

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight.

Phosphate homeostasis is essential for health and is achieved via interaction between the bone, kidney, small intestine, and parathyroid glands and via intricate processes involving phosphate transporters, phosphate sensors, and circulating hormones. Numerous genetic and acquired disorders are associated with disruption in these processes and can lead to significant morbidity and mortality. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans are different. Intestinal phosphate transport also appears to differ in humans and rodents, with recent studies demonstrating a dominant role for the paracellular pathway. The existence of phosphate sensing has been acknowledged for decades; however, the underlying molecular mechanisms are poorly understood. At least three phosphate sensors have emerged. PiT2 and FGFR1c both act as phosphate sensors controlling Fibroblast Growth Factor 23 secretion in bone, whereas the calcium-sensing receptor controls parathyroid hormone secretion in response to extracellular phosphate. All three of the proposed sensors are expressed in the kidney and intestine but their exact function in these organs is unknown. Understanding organ interactions and the mechanisms involved in phosphate sensing requires significant research to develop novel approaches for the treatment of phosphate homeostasis disorders.

Performance of ion chromatography to measure picomole amounts of magnesium in nanolitre samples.

KEY POINTS: An UHPLC method to measure picomole amounts of magnesium has been developed. The method is sensitive, specific, accurate and reproducible. The method is suitable for quantifying magnesium transport across intact epithelia. ABSTRACT: Magnesium is involved in many biological processes. Extracellular magnesium homeostasis mainly depends on the renal handling of magnesium, the study of which requires measurement of low concentrations of magnesium in renal tubular fluid. We developed an ultra-high-performance liquid chromatography method to measure millimolar concentrations of magnesium in nanolitre samples. Within-assay and between-assay coefficients of variation were lower than 5% and 6.6%, respectively. Measurement of magnesium concentration was linear (r2  = 0.9998) over the range 0-4 mmol/l. Absolute bias ranged from -0.03 to 0.05 mmol/l. The lower limit of quantification was 0.2 mmol/l. Recovery was 97.5-100.3%. No significant interference with calcium, another divalent cation present in the same samples, was detected. The method was successfully applied to quantify transepithelial magnesium transport by medullary and cortical thick ascending limbs during ex vivo microperfusion experiments. In conclusion, ultra-high-performance liquid chromatography is suitable for measurement of picomole amounts of magnesium in renal tubular fluid. The method allows detailed studies of transepithelial magnesium transport across native epithelium.

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

BACKGROUND: Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. METHODS: Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months. RESULTS: After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. CONCLUSIONS: This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.

Medullary and cortical thick ascending limb: similarities and differences.

The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with different composition of the peritubular environment. The TAL plays a critical role in the control of NaCl, water, acid, and divalent cation homeostasis, as illustrated by the consequences of the various monogenic diseases that affect the TAL. It delivers tubular fluid to the distal convoluted tubule and thereby affects the function of the downstream tubular segments. The TAL is commonly considered as a whole. However, many structural and functional differences exist between its medullary and cortical parts. The present review summarizes the available data regarding the similarities and differences between the medullary and cortical parts of the TAL. Both subsegments reabsorb NaCl and have high Na+-K+-ATPase activity and negligible water permeability; however, they express distinct isoforms of the Na+-K+-2Cl- cotransporter at the apical membrane. Ammonia and bicarbonate are mostly reabsorbed in the medullary TAL, whereas Ca2+ and Mg2+ are mostly reabsorbed in the cortical TAL. The peptidic hormone receptors controlling transport in the TAL are not homogeneously expressed along the cortical and medullary TAL. Besides this axial heterogeneity, structural and functional differences are also apparent between species, which underscores the link between properties and role of the TAL under various environments.

Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion.

The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood. Here we evaluated the role of the inwardly rectifying potassium channel subunit Kir4.2 (Kcnj15 gene product) in this process. In mice, Kir4.2 was present exclusively at the basolateral membrane of proximal tubular cells and disruption of Kcnj15 caused a hyperchloremic metabolic acidosis associated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubule dysfunction. Urinary ammonium excretion rates in Kcnj15- deleted mice were inappropriate to acidosis under basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transporters in the collecting duct. In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximal cells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase enzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15-deleted mice. Additionally, Kcnj15 deletion depolarized the proximal cell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization. Thus, the Kir4.2 potassium channel subunit is a newly recognized regulator of proximal ammonia metabolism. The kidney consequences of its loss of function in mice support the proposal for KCNJ15 as a molecular basis for human isolated proximal renal tubular acidosis.

Survival and specific outcome of sickle cell disease patients after renal transplantation.

The prognosis of sickle cell disease (SCD) patients who need dialysis is poor, but experience with kidney transplantation is limited. This study assessed the characteristics of 36 SCD patients undergoing renal transplantation. Immediate post-surgical complications occurred in 25% of cases. Cytomegalovirus and bacterial infections were frequently observed. Twelve patients died after a median follow-up period of 17·4 months. Overall patient survival was significantly lower in SCD than in the control group without significant difference for overall death-censored graft survival. Our data suggest that renal transplantation should be systematically considered in SCD patients with end-stage renal disease.

An Open-Label Phase 2 Study of Eneboparatide, a Novel PTH Receptor 1 Agonist, in Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is a rare disorder characterized by a deficiency in parathyroid hormone (PTH) resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. Eneboparatide is an investigational peptide agonist of the PTH1 receptor for the treatment of chronic hypoparathyroidism (HP). OBJECTIVE: To evaluate the efficacy, safety, and tolerability of eneboparatide in HP patients. DESIGN: Open-label, phase 2 study. PARTICIPANTS: Twenty-eight patients (21 women, 7 men), mean age (range): 58 years (28-72), with HP were enrolled into 2 consecutive cohorts (C1, n = 12, and C2, n = 16). INTERVENTION: Following an optimization period, daily subcutaneous injections of eneboparatide were administered for 3 months at 20 µg/day (C1) or 10 µg/day (C2) starting dose. Conventional therapy was progressively removed and eneboparatide could be titrated up to 60 µg (C1) or 80 µg (C2). MAIN OUTCOMES: Proportion of patients achieving independence from conventional therapy, albumin-adjusted serum calcium (ADsCa), 24-h urine calcium (uCa), serum bone turnover markers (s-CTX and P1NP), bone mineral density (BMD), and adverse events (AEs). RESULTS: After 3 months, ≥ 88% patients achieved independence from conventional therapy while mean ADsCa was maintained within target range (7.8-9 mg/dL). Eneboparatide induced a rapid and sustained reduction of mean 24-hour uCa, even among patients with hypercalciuria. Bone turnover markers slightly increased and BMD remained unchanged, consistent with progressive resumption of physiologic bone turnover. Eneboparatide was well tolerated with no serious AEs. CONCLUSION: Eneboparatide allowed independence from conventional therapy and maintenance of serum calcium within a target range, while normalizing uCa excretion and producing a balanced resumption of bone turnover.

Effects of parathyroidectomy on kidney function in patients with primary hyperparathyroidism: Results of a prospective study.

BACKGROUND: Altered glomerular filtration rate is a controversial indication for parathyroidectomy in patients with primary hyperparathyroidism. The objective of this study was to evaluate the estimated glomerular filtration rate change 12 months after parathyroidectomy for primary hyperparathyroidism according to preoperative kidney function. METHOD: Patients who underwent parathyroidectomy for primary hyperparathyroidism between 2016 and 2021 (n = 381) were enrolled in a monocentric prospective cohort. Patients without 1-year follow-up or with missing data were excluded (n = 135, 35%). Patients were dichotomized according to their baseline estimated glomerular filtration rate: <60 mL/min (group 1) and ≥60 mL/min (group 2). Parameters were measured before and then at 6 and 12 months after parathyroidectomy. RESULTS: Out of 246 included patients, 27 (11%) were assigned to group 1 and 219 (89%) to group 2. The mean baseline estimated glomerular filtration rate was 46.8 ± 11.5 and 87.3 ± 14.7 mL/min in groups 1 and 2, respectively. Group 1 patients were older (P = .0006) and had a higher median serum parathyroid hormone level (P = .021). At 6 months postoperative, 224 patients (91%) were normocalcemic. The estimated glomerular filtration rate raw change after parathyroidectomy was significantly higher in group 1 than in group 2 (4.2 ± 7.8 vs -2.2 ± 9.1 mL/min, P = .0004). In group 1, 13/27 patients (48%) improved their chronic kidney disease stage after parathyroidectomy, including 6/13 (46%) with postoperative estimated glomerular filtration rate ≥60 mL/min, whereas 2/27 (7%) worsened. The baseline estimated glomerular filtration rate <60 mL/min and elevated serum calcium level were associated with postoperative estimated glomerular filtration rate improvement in multivariable analysis (P = .0023 and .039, respectively). CONCLUSION: Parathyroidectomy for primary hyperparathyroidism is more likely to improve kidney function in patients with preoperative estimated glomerular filtration rate <60 mL/min. These results strengthen the current guidelines for surgery.

Calcium homeostasis and hyperparathyroidism: Nephrologic and endocrinologic points of view.

Parathyroid hormone (PTH) is a hypercalcemic hormone acting on kidneys, bone and intestine. PTH promotes calcium release from the bone, renal calcium reabsorption and phosphate excretion, and conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D-3. Hyperparathyroidism consists in PTH elevation, which may be adapted (secondary hyperparathyroidism) or non-adapted to calcemia levels (primary hyperparathyroidism, familial hypercalcemia/hypocalciuria, tertiary hyperparathyroidism). Primary hyperparathyroidism (PHP) features hypercalcemia and elevated or inappropriate PTH elevation. PHP may be revealed by biological abnormalities such as hypercalcemia and can be accompanied by renal complications (hypercalciuria, nephrolithiasis, nephrocalcinosis) and/or osteoporosis. However, it can also be normocalcemic and calcium loading will be necessary to diagnosis it. The differential diagnosis of PHP is familial hypocalciuric hypercalcemia (FHH), a dominant autosomal disease implicating a calcium sensing receptor-inactivating mutation. It impairs parathyroid cell sensitivity to calcemia elevation and thus induces excessive PTH stimulation, leading to hypercalcemia. Secondary HP (SHP) consists in PTH elevation secondary to a stimulus that needs to be corrected. 25 OHvitD deficiency, kidney failure, renal hypercalciuria, malabsorption and some drugs can induce SHP. Tertiary HP (THP) consists in autonomous PTH secretion by the parathyroid glands after prolonged stimulation under SHP, of whatever cause. This parathyroid autonomy results from the polyclonal hyperplasia observed in SHP progressing toward monoclonal nodular proliferation, leading to nodular hyperplasia or parathyroid adenoma (or, exceptionally, carcinoma), with reduced expression of CaSR and vitamin D receptor. In patients under dialysis, the frontier between SHP and THP is a matter of debate. This review will focus on the pathophysiology of calcium, diagnosis, and management of hyperparathyroidism.

[Genetic screening is essential in polycystic kidney disease: It is never too late!] / Une polykystose peut en cacher une autre. Il n'est jamais trop tard pour l'analyse génétique !

In France, numerous patients suffered from chronic kidney disease on polycystic kidney disorder. If PKD1 and PKD2 inactivating mutations are the most prevalent, several other genetic polycystic kidney diseases are responsible for similar kidney features and may be associated with severe extrarenal phenotypes. Genetic analysis in front of a polycystic disorder is not systematic, but is essential to assess the genetic diagnosis, discuss the intensity of treatment (vaptan) and precise the prognostic and the transmission of the phenotype. We detailed the case of a patient with end stage renal disease due to a polycystic kidney disease. Genetic analysis at 70 year of age revealed an oral-facial-digital syndrome type 1. The diagnosis had an important impact in the familial history and to attach the extrarenal phenotype to the syndrome. Our case illustrates that, in front of a polycystic kidney disease (even in aged patients with end stage renal disease) genetic screening is essential, for the propositus and their family and to take care of the extrarenal manifestations.

Complex Management of Nephrotic Syndrome and Kidney Failure during Pregnancy in a Type 1 Diabetes Patient: A Challenging Case.

Pregnancy with chronic kidney disease is challenging, and patients with diabetic nephropathy are at particular risk of a rapid kidney function decline during pregnancy. While indications for the management of pregnant patients with initial diabetic nephropathy are widely available in the literature, data on patients with severe nephrotic syndrome and kidney function impairment are lacking, and the decision on whether and when dialysis should be initiated is not univocal. We report a type 1 diabetes patient who started pregnancy with a severe nephrotic syndrome and shifted from CKD stage 3b to stage 5 during pregnancy. The management was complicated by a fetal heart malformation and by poorly controlled diabetes. The evidence for and against starting dialysis was carefully evaluated, and the choice of strict nephrological and obstetrical monitoring, nutritional management, and diuretic treatment made it possible to avoid dialysis in pregnancy, after ruling out pre-eclampsia. This experience enables examination of some open issues and contributes to the discussion of when to start dialysis in pregnancy.

Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real-world Data Results from the AlcalUN Study.

Oral alkalization with sodium bicarbonate (NaHCO3 ) or citrate is prescribed for conditions ranging from metabolic acidosis to nephrolithiasis. Although most nephrologists/urologists use this method routinely, extracellular volume (ECV) increase is the main feared adverse event reported for NaHCO3 . Thus far, no trial has specifically studied this issue in a real-world setting. AlcalUN (NCT03035812) is a multicentric, prospective, open-label cohort study with nationwide (France) enrollment in 18 (public and private) nephrology/urology units. Participants were adult outpatients requiring chronic (>1 month) oral alkalization by either NaHCO3 -containing or no-NaHCO3 -containing agents. The ECV increase (primary outcome) was judged based on body weight increase (ΔBW), blood pressure increase (ΔBP), and/or new-onset edema at the first follow-up visit (V1). From February 2017 to February 2020, 156 patients were enrolled. After a median 106 days of treatment, 91 (72%) patients reached the primary outcome. They had lower systolic (135 (125, 141) vs. 141 (130, 150), P = 0.02) and diastolic (77 (67, 85) vs. 85 (73, 90), P = 0.03) BP values, a higher plasma chloride (106.0 (105.0, 109.0) vs. 105.0 (102.0, 107.0), P = 0.02) at baseline, and a less frequent history of nephrolithiasis (32 vs. 56%, P = 0.02). Patients experienced mainly slight ΔBP (< 10 mmHg). The primary outcome was not associated (P = 0.79) with the study treatment (129 received NaHCO3 and 27 received citrate). We subsequently developed three different models of propensity score matching; each confirmed our results. Chronic oral alkalization with NaHCO3 is no longer associated with an ECV increase compared to citrate in real-life settings.