The role of fibroblast growth factor 23 in regulation of phosphate balance.

Phosphate is essential for numerous biological processes, and serum levels are tightly regulated to accomplish these functions. The regulation of serum phosphate in a narrow physiological range is a well-orchestrated process and involves the gastrointestinal (GI) tract, bone, kidneys, and several hormones, namely, parathyroid hormone, fibroblast growth factor 23 (FGF23), and 1,25-dihydroxyvitamin D (1,25 Vitamin D). Although primarily synthesized in the bone, FGF23, an endocrine FGF, acts on the kidney to regulate phosphate and Vitamin D homeostasis by causing phosphaturia and reduced levels of 1,25 Vitamin D. Recent studies have highlighted the complex regulation of FGF23 including transcriptional and post-translational modification and kidney-bone cross talk. Understanding FGF23 biology has led to the identification of novel therapeutic agents to treat diseases that disrupt phosphate metabolism secondary to FGF23. The focus of this review is to provide an overview of phosphate homeostasis, FGF23 biology, and the role of FGF23 in phosphate balance.

C3 glomerulopathy in a patient with a history of post-infectious glomerulonephritis.

Post-infectious glomerulonephritis (PIGN) is an immune complex mediated glomerular injury occurring because of an infection, most commonly with group A beta-hemolytic streptococcus in children. C3 glomerulopathy (C3G) is a distinct clinicopathological entity occurring secondary to dysregulation of alternate complement pathway encompassing both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). While most patients with PIGN attain complete remission with normalized complement levels by 6-8 weeks after presentation, patients with C3G continue to have hypocomplementemia with high rates of progressive kidney disease. Here, we report a patient diagnosed with dense deposit disease after his initial presentation with PIGN three years prior. While current literature continues to explore the overlapping and distinguishing features of PIGN and C3G, including how underlying defects in the alternate complement pathway may commonly contribute to both diseases, this case further exemplifies the importance of recognizing the clinico-pathogenic features of PIGN and C3G in pediatric patients with glomerulonephritis.

Acetaminophen induced high anion gap metabolic acidosis: a potentially under-recognized consequence from a common medication.

While metabolic acidosis is one of the most common complications in patients with chronic kidney disease (CKD), there are several uncommon etiologies that are challenging to diagnose. Here, we describe a patient on peritoneal dialysis who developed high anion gap metabolic acidosis secondary to acquired 5-oxoprolinemia from acetaminophen use. While CKD is a known risk factor for developing this potentially serious complication, this case further highlights how 5-oxoproline accumulation can occur, even with therapeutic dosing of acetaminophen.

Use of ClearGuard HD caps in pediatric hemodialysis patients.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of hospitalizations and mortality among patients receiving hemodialysis (HD) therapy, especially those with a central venous catheter (CVC) for dialysis access. The use of chlorhexidine impregnated catheter caps (ClearGuard) has been associated with a decrease in the rate of HD catheter-related BSIs (CA-BSIs) in adults; similar data have not been published for children. METHODS: We compared CA-BSI data from participating centers within the Standardizing Care to Improve Outcomes in Pediatric Endstage Kidney Disease (SCOPE) collaborative based on the center's use of ClearGuard caps for patients with HD catheter access. Centers were characterized as ClearGuard (CG) or non-ClearGuard (NCG) centers, with CA-BSI data pre- and post-CG implementation reviewed. All positive blood cultures in participating centers were reported to the SCOPE collaborative and adjudicated by an infectious disease physician. RESULTS: Data were available from 1786 SCOPE enrollment forms completed January 2016-January 2022. January 2020 served as the implementation date for analyzing CG versus NCG center data, with this being the time when the last CG center underwent implementation. Post January 2020, there was a greater decrease in the rate of HD CA-BSI in CG centers versus NCG centers, with a decrease from 1.18 to 0.23 and 0.41 episodes per 100 patient months for the CG and NCG centers, respectively (p = 0.002). CONCLUSIONS: Routine use of ClearGuard caps in pediatric dialysis centers was associated with a reduction of HD CA-BSI rates in pediatric HD patients.

Clinicopathological features of C3 glomerulopathy in children: a single-center experience.

BACKGROUND: C3 glomerulopathy (C3G) is defined by dominant glomerular deposition of C3 and minimal or no immunoglobulin, with two subtypes-dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)-distinguished by features on electron microscopy (EM). Given that this rare disease has generally unfavorable yet highly variable outcomes, we sought out to review the histopathology, complement/genetic studies, and renal outcomes of pediatric patients with C3G at our institution. METHODS: All native kidney biopsies performed in a single pediatric hospital over a 10-year period were reviewed for features of C3G. Of 589 biopsy reports, we identified 9 patients fulfilling the diagnostic criteria for C3G and retrospectively reviewed their clinical chart and renal biopsy findings. RESULTS: We identified 4 patients with DDD, 4 with C3GN, and 1 indeterminate case, with features of both C3GN and DDD. Five patients were positive for one or more nephritic factors (C3NeF, C4NeF, C5NeF) with 1 patient additionally positive for complement factor H (CFH) autoantibody. Genetic testing done in 5 of the 9 patients failed to identify any causative mutations. Three patients showed progressive renal dysfunction over a mean follow-up period of 33 months. CONCLUSIONS: Complement and genetic studies are now routinely recommended for patients with a histopathological diagnosis of C3G. Careful interpretation of these studies and their prognostic and therapeutic implications in conjunction with biopsy findings is needed to further understand the pathophysiology of this rare disease in children.

Phenotypic severity scoring system and categorisation for prune belly syndrome: application to a pilot cohort of 50 living patients.

OBJECTIVE: To design a novel system of scoring prune belly syndrome (PBS) phenotypic severity at any presenting age and apply it to a large pilot cohort. PATIENTS AND METHODS: From 2000 to 2017, patients with PBS were recruited to our prospective PBS study and medical records were cross-sectionally analysed, generating individualised RUBACE scores. We designed the pragmatic RUBACE-scoring system based on six sub-scores (R: renal, U: ureter, B: bladder/outlet, A: abdominal wall, C: cryptorchidism, E: extra-genitourinary, generating the acronym RUBACE), yielding a potential summed score of 0-31. The 'E' score was used to segregate syndromic PBS and PBS-plus variants. The cohort was scored per classic Woodard criteria and RUBACE scores compared to Woodard category. RESULTS: In all, 48 males and two females had a mean (range) RUBACE score of 13.8 (8-25) at a mean age of 7.3 years. Segregated by phenotypic categories, there were 39 isolated PBS (76%), six syndromic PBS (12%) and five PBS-plus (10%) cases. The mean RUBACE scores for Woodard categories 1, 2, and 3 were 20.5 (eight patients), 13.8 (25), and 10.6 (17), respectively (P < 0.001). CONCLUSIONS: RUBACE is a practical, organ/system level, phenotyping tool designed to grade PBS severity and categorise patients into isolated PBS, syndromic PBS, and PBS-plus groups. This standardised system will facilitate genotype-phenotype correlations and future prospective multicentre studies assessing medical and surgical treatment outcomes.

Donation after cardiac death kidneys are suitable for pediatric recipients.

Despite the high number of children listed for kidney transplantation and shortage of deceased organ donors, there is reluctance to utilize DCD kidneys in pediatric recipients. We examined outcomes in pediatric kidney transplant patients who received a DCD kidney allograft. UNOS database was queried to examine outcomes in all pediatric kidney transplant recipients from 1994 to 2017. Pediatric status was defined as <18 years at the time of transplantation. Recipients were divided by DBD or DCD allograft status. Donor and recipient demographic data were examined. Patient and allograft survival was calculated, and Kaplan-Meier survival curves were generated. A P-value of <0.05 was considered to be significant. A total of 286 pediatric kidney transplant recipients received a DCD allograft. The donors in the DCD group were significantly younger than those in the DBD group (21.7 vs 23.3 years), with a higher KDPI (26.5% vs 22.9%). In the DCD group, the average age at transplant was younger (11.6 vs 12.9 years), with no difference in cold ischemia time or length of stay between the two groups. Rates of delayed graft function were higher in the DCD group, but despite this, there were no significant differences in allograft or patient survival between the groups. There is no difference in allograft survival in pediatric kidney transplant recipients who receive a DCD kidney allograft. DCD kidney allografts are suitable for transplantation in pediatric patients and can greatly expand the donor pool.

Utilizing increased risk for disease transmission (IRD) kidneys for pediatric renal transplant recipients.

BACKGROUND: Strategies to expand numbers of deceased donor kidneys suitable for pediatric recipients are urgently needed to prevent long-term dialysis-associated morbidity and mortality. Donors designated as increased risk of disease transmission (IRD) are infrequently used in pediatric recipients. We examined outcomes of these kidneys in pediatric patients and the potential to increase the donor pool. METHODS: The United Network for Organ Sharing (UNOS) database records presence of IRD in all deceased donors since 2004. All pediatric kidney transplant recipients from 2004 to 2017 were identified and stratified by IRD status, and outcomes were examined. RESULTS: Four hundred seventy-three pediatric kidney transplant recipients received an IRD allograft. IRD donors had lower kidney donor profile index (KDPI); were more likely to be younger, male, and Caucasian; and were more likely to have used drugs. IRD kidneys were more likely to have been biopsied and placed on pulsatile perfusion. Other than an older recipient age, demographic data were not different between groups. Allograft and patient survivals were similar, as were rejection and delayed graft function rates. Compared with adult recipients and adult IRD recipients, pediatric recipients were more likely to have a younger donor, receive a kidney with a lower creatinine, and were less likely to have delayed graft function (p < 0.05). There were no recorded disease transmissions in IRD group. CONCLUSIONS: Patient and allograft survivals are similar in IRD and non-IRD kidneys. High-quality IRD organs used in adults represent a large number of donors with excellent outcomes. IRD allografts have a potential to increase transplant volume and should be considered for pediatric patients.

Proteinuria and hematuria in the neonate.

PURPOSE OF REVIEW: Neonatal proteinuria and hematuria while not common can have potentially devastating consequences if left undiagnosed and untreated. It is important to distinguish between inherited and acquired causes of proteinuria to initiate appropriate and timely treatment. With regards to hematuria, it is critical to identify true hematuria from pseudo-hematuria to balance between thorough investigation and unnecessary laboratory work up. This review provides an overview of the common causes of hematuria and proteinuria in a neonate. RECENT FINDINGS: The identification of genetic mutations in nephrotic syndrome has improved our understanding of the role of various proteins that play an important role in maintaining the glomerular filtration barrier. With the advancement in our ability to provide care for extreme premature neonates, the incidence of acute kidney injury has increased in these neonates along with proteinuria and hematuria. SUMMARY: Persistent proteinuria after neonatal acute kidney injury would be of interest in regards to the risk of developing future chronic kidney disease and hypertension.

Renal NHE expression and activity in neonatal NHE3- and NHE8-null mice.

Na(+)/H(+) exchanger (NHE)3 is the predominant NHE on the brush-border membrane of the proximal tubule in adult animals. NHE8 has been localized to the brush-border membrane of proximal tubules and is more highly expressed in neonates than in adult animals. However, the relative role of NHE8 in neonatal renal acidification is unclear. The present study examined if there was a compensatory increase in NHE3 in NHE8-null neonatal mice and whether there was a compensatory increase in NHE8 in NHE3-null neonatal mice. In addition, we examined whether wild-type, NHE3-null, and NHE8-null mice had an increase in NHE activity in response to metabolic acidosis. We found that at baseline, there was comparable renal NHE3 mRNA, total protein, and brush-border membrane protein abundance as in neonatal control and NHE8-null mice. There was comparable renal NHE8 mRNA, total protein, and brush-border membrane protein abundance in NHE3-null neonatal and control mice. Both NHE3- and NHE8-null mice had a comparable but lower rate of NHE activity than control mice. We next imposed metabolic acidosis in wild-type, NHE3-null, and NHE8-null mice. Acidemic NHE8-null mice had an increase in brush-border membrane vesicle NHE3 protein abundance and NHE activity compared with vehicle-treated mice. Likewise, NHE3-null mice had an increase in NHE8 brush-border membrane protein abundance and NHE activity in response to metabolic acidosis. In conclusion, both NHE3 and NHE8 likely play a role in neonatal acidification.

Effect of prenatal programming and postnatal rearing on glomerular filtration rate in adult rats.

The present study examined whether a prenatal low-protein diet programs a decrease in glomerular filtration rate (GFR) and an increase in systolic blood pressure (BP). In addition, we examined whether altering the postnatal nutritional environment of nursing neonatal rats affected GFR and BP when rats were studied as adults. Pregnant rats were fed a normal (20%) protein diet or a low-protein diet (6%) during the last half of pregnancy until birth, when rats were fed a 20% protein diet. Mature adult rats from the prenatal low-protein group had systolic hypertension and a GFR of 0.38 ± 0.03 versus 0.57 ± 0.05 ml·min(-1)·100 g body wt(-1) in the 20% group (P < 0.01). In cross-fostering experiments, mothers continued on the same prenatal diet until weaning. Prenatal 6% protein rats cross-fostered to a 20% mother on day 1 of life had a GFR of 0.53 ± 0.05 ml·min(-1)·100 g body wt(-1), which was not different than the 20% group cross-fostered to a different 20% mother (0.45 ± 0.04 ml·min(-1)·100 g body wt(-1)). BP in the 6% to 20% group was comparable with the 20% to 20% group. Offspring of rats fed either 20% or 6% protein diets during pregnancy and cross-fostered to a 6% mother had elevated BP but a comparable GFR normalized to body weight as the 20% to 20% control group. Thus, a prenatal low-protein diet causes hypertension and a reduction in GFR in mature adult offspring, which can be modified by postnatal rearing.

Developmental changes in renal tubular transport-an overview.

The adult kidney maintains a constant volume and composition of extracellular fluid despite changes in water and salt intake. The neonate is born with a kidney that has a small fraction of the glomerular filtration rate of the adult and immature tubules that function at a lower capacity than that of the mature animal. Nonetheless, the neonate is also able to maintain a constant extracellular fluid volume and composition. Postnatal renal tubular development was once thought to be due to an increase in the transporter abundance to meet the developmental increase in glomerular filtration rate. However, postnatal renal development of each nephron segment is quite complex. There are isoform changes of several transporters as well as developmental changes in signal transduction that affect the capacity of renal tubules to reabsorb solutes and water. This review will discuss neonatal tubular function with an emphasis on the differences that have been found between the neonate and adult. We will also discuss some of the factors that are responsible for the maturational changes in tubular transport that occur during postnatal renal development.

Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D3 [1,25(OH)2 Vitamin D3]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1-4 with "b" and "c" isoforms for receptors 1, 2, and 3. FGFR1, 3, and 4 are expressed in the mouse proximal tubule, and deletion of any one receptor did not affect serum phosphate levels, suggesting that more than one receptor is involved in mediating the phosphaturic actions of FGF23. To determine the receptors responsible for the phosphaturic actions of FGF23, we studied Fgfr1 (kidney conditional) and Fgfr4 (global) double mutant mice (Fgfr1⁻/⁻/Fgfr4⁻/⁻). Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have higher FGF23 levels than their wild-type counterparts (108.1 ± 7.3 vs. 4,953.6 ± 675.0 pg/ml; P < 0.001). Despite the elevated FGF23 levels, Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have elevated serum phosphorus levels, increased brush-border membrane vesicle (BBMV) phosphate transport, and increased Na-P(i) cotransporter 2c (NaPi-2c) protein expression compared with wild-type mice. These data are consistent with FGFR1 and FGFR4 being the critical receptors for the phosphaturic actions of FGF23.

Inherited disorders of calcium and phosphate metabolism.

PURPOSE OF REVIEW: Inherited disorders of calcium and phosphate homeostasis have variable presentation and can cause significant morbidity. An understanding of the mode of inheritance and pathophysiology of these conditions will help in the diagnosis and early institution of therapy. RECENT FINDINGS: Identification of genetic mutations in humans and animal models has advanced our understanding of many inherited disorders of calcium and phosphate regulation. Identification of mutations of calcium-sensing receptor has improved our understanding of hypocalcemic and hypercalcemic conditions. Mutations of Fgf23, Klotho and phosphate transporter genes have been identified to cause disorders of phosphate metabolism. SUMMARY: Calcium and phosphate homeostasis is tightly regulated in a narrow range due to their vital role in many biological processes. Inherited disorders of calcium and phosphate metabolism though uncommon can have severe morbidity. Genetic counseling of the affected families is an important part of the follow-up of these patients.

Complement disorders and hemolytic uremic syndrome.

PURPOSE OF REVIEW: Complement mediated hemolytic uremic syndrome (aHUS) accounts for a significant proportion of non-shiga toxin HUS. The purpose of this review is to outline the pathophysiology, clinical features and therapeutic options for aHUS. RECENT FINDINGS: In the last decade, strides have been made in identifying several new disease-causing mutations in complement-regulating proteins. SUMMARY: Complement mediated HUS (aHUS) has a worse prognosis compared with shiga toxin mediated HUS, often resulting in end stage renal disease. Early identification of aHUS is crucial so that plasma therapy can be initiated. After renal transplantation, there is very high risk of disease recurrence and graft loss. Eculizumab and combined liver-kidney transplantation offer promise for improved prognosis.

Acid increases NHE8 surface expression and activity in NRK cells.

We previously demonstrated that there is a paucity of brush-border membrane NHE3 in neonates, the predominant Na(+)/H(+) exchanger in the adult proximal tubule, while NHE8 is relatively highly expressed in neonates compared with adults. We recently showed that metabolic acidosis in neonatal rodents can increase brush-border membrane NHE8 protein expression and Na(+)/H(+) exchange activity. To further examine the regulation of NHE8 by acid, we incubated NRK cells, which express NHE8 but not NHE3, with either acid or control media (6.6 vs. 7.4). There was an increase in Na(+)/H(+) exchanger activity within 6 h of incubation with acid media assessed as the rate of sodium-dependent recovery of pH from an acid load (dpH(i)/dt). The acid stimulation persisted for at least 24 h. The increase in Na(+)/H(+) exchange activity was paralleled by an increase in surface expression of NHE8, assessed by surface biotinylation and streptavidin precipitation. The increase in both apical membrane NHE8 protein expression and Na(+)/H(+) exchange activity with pH 6.6 media compared with 7.4 media was not affected by actinomycin D or cycloheximide consistent with an increase in surface expression independent of mRNA or protein synthesis. Furthermore, there was no increase in total cellular NHE8 protein abundance or mRNA abundance with acid media. Finally, we demonstrate that the increase in surface expression of NHE8 with acid media was blocked by colchicine and cytochalasin D and mediated by acid increasing the rate of exocytosis. In conclusion, NHE8 surface expression and activity are regulated by acid media by increasing the rate of trafficking to the apical membrane.

Proximal tubule Na+/H+ exchanger activity in adult NHE8-/-, NHE3-/-, and NHE3-/-/NHE8-/- mice.

NHE3 is the predominant Na(+)/H(+) exchanger on the brush-border membrane (BBM) of the proximal tubule in adults. However, NHE3 null mice still have significant renal BBM Na(+)/H(+) activity. NHE8 has been localized to the BBM of proximal tubules and is more highly expressed in neonates than adult animals. The relative role of NHE8 in adult renal H(+) transport is unclear. This study examined whether there was compensation by NHE8 in NHE3(-/-) mice and by NHE3 in NHE8(-/-) mice. NHE3(-/-) mice had significant metabolic acidosis, and renal BBM NHE8 protein abundance was greater in NHE3(-/-) mice than control mice, indicating that there may be compensation by NHE8 in NHE3(-/-) mice. NHE8(-/-) mice had serum bicarbonate levels and pH that were not different from controls. NHE3 protein expression on the BBM was greater in NHE8(-/-) mice than in wild-type mice, indicating that there may be compensation by NHE3 in NHE8(-/-) mice. Both BBM NHE3 and NHE8 protein abundance increased in response to acidosis. Blood pressure and Na(+)/H(+) exchanger activity were comparable in NHE8(-/-) mice to that of controls, but both were significantly lower in NHE3(-/-) mice compared with control mice. Compared with NHE3(-/-) mice, NHE3(-/-)/NHE8(-/-) mice had lower blood pressures. While serum bicarbonate was comparable in NHE3(-/-) mice and NHE3(-/-)/NHE8(-/-) mice, proximal tubule Na(+)/H(+) exchange activity was less in NHE3(-/-)/NHE8(-/-) mice compared with NHE3(-/-) mice. In conclusion, NHE3 is the predominant Na(+)/H(+) exchanger in adult mice. NHE8 may play a compensatory role in renal acidification and blood pressure regulation in NHE3(-/-) mice.

Genetic disorders of phosphate regulation.

Regulation of phosphate homeostasis is critical for many biological processes, and both hypophosphatemia and hyperphosphatemia can have adverse clinical consequences. Only a very small percentage (1%) of total body phosphate is present in the extracellular fluid, which is measured by routine laboratory assays and does not reflect total body phosphate stores. Phosphate is absorbed from the gastrointestinal tract via the transcellular route [sodium phosphate cotransporter 2b (NaPi2b)] and across the paracellular pathway. Approximately 85% of the filtered phosphate is reabsorbed from the kidney, predominantly in the proximal tubule, by NaPi2a and NaPi2c, which are present on the brush border membrane. Renal phosphate transport is tightly regulated. Dietary phosphate intake, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D3, and fibroblast growth factor 23 (FGF23) are the principal regulators of phosphate reabsorption from the kidney. Recent advances in genetic techniques and animal models have identified many genetic disorders of phosphate homeostasis. Mutations in NaPi2a and NaPi2c; and hormonal dysregulation of PTH, FGF23, and Klotho, are primarily responsible for most genetic disorders of phosphate transport. The main focus of this educational review article is to discuss the genetic and clinical features of phosphate regulation disorders and provide understanding and treatment options.

The mammalian SKIV2L RNA exosome is essential for early B cell development.

The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell-specific Skiv2l knockout mice (Skiv2lfl/flCd79a-Cre), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro-B cell to large pre-B cell transition. Mechanistically, Skiv2l-deficient pro-B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of µH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.