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Background: Primary cilia regulation of renal function and BP in health and disease is incompletely understood. This study investigated the effect of nephron ciliary loss on renal physiology, BP, and ensuing cystogenesis., Methods: Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the Ift88 gene at 2 months of age using a Cre-LoxP strategy. BP, kidney function, and renal pathology were studied 2 and 9 months after DOX (Ift88 KO) or vehicle (control)., Results: At 2 months post-DOX, male, but not female, Ift88 KO, compared with sex-matched control, mice had reduced BP, enhanced salt-induced natriuresis, increased urinary nitrite and nitrate (NOx) excretion, and increased kidney NOS3 levels, which localized to the outer medulla; the reductions in BP in male mice were prevented by L-NAME. At 9 months post-DOX, male, but not female, Ift88 KO mice had polycystic kidneys, elevated BP, and reduced urinary NOx excretion. No differences were observed in plasma renin concentration, plasma aldosterone, urine vasopressin, or urine PGE 2 between Ift88 KO and control mice at 2 or 9 months post-DOX., Conclusions: Nephron cilia disruption in male, but not female, mice ( 1 ) reduces BP prior to cyst formation, ( 2 ) increases NOx production that may account for the lower BP prior to cyst formation, and ( 3 ) induces polycystic kidneys that are associated with hypertension and reduced renal NO production., (Copyright © 2021 by the American Society of Nephrology.)

Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a central role in maintaining serum magnesium within a narrow range (0.70-1.10 mmol/L). Along the proximal tubule and thick ascending limb, magnesium reabsorption occurs via paracellular pathways. Members of the claudin family form the magnesium pores in these segments, and also regulate magnesium reabsorption by adjusting the transepithelial voltage that drives it. Along the distal convoluted tubule transcellular reabsorption via heteromeric TRPM6/7 channels predominates, although paracellular reabsorption may also occur. In this segment, the NaCl cotransporter plays a critical role in determining transcellular magnesium reabsorption. Although the general machinery involved in renal magnesium reabsorption has been identified by studying genetic forms of magnesium imbalance, the mechanisms regulating it are poorly understood. This review discusses pathways of renal magnesium reabsorption by different segments of the nephron, emphasizing newer findings that provide insight into regulatory process, and outlining critical unanswered questions., (Copyright © 2021 by the American Society of Nephrology.)

Background: There are limited data concerning patients treated with sequential bilateral kidney surgery. Current guidelines still lack an optimal surgical sequencing approach. We evaluated renal functional outcomes after sequential partial nephrectomy (PN) and radical nephrectomy (RN) in patients with bilateral renal cell carcinoma (RCC)., Methods: A propensity score matched cohort of 267 patients (synchronous bilateral RCCs, N = 44 [88 lesions]; metachronous bilateral, N = 45 [90 lesions]; unilateral, N = 178) from two tertiary institutions were retrospectively analyzed. Synchronous bilateral RCCs were defined as diagnosis concomitantly or within 3 months of former tumor. Renal functional outcomes were defined as estimated glomerular filtration rate (eGFR) changes and de novo chronic kidney disease (CKD, stage ≥3) after surgery. Renal functional outcomes and clinical factors predicting de novo CKD were assessed using descriptive statistics and Cox regression analysis., Results: In subgroup of bilateral RCCs, patients underwent sequential PN (N = 48), PN followed by RN (N = 8), or RN followed by PN (N = 25). Final postoperative estimated glomerular filtration rates (eGFRs) were 79.4, 41.4, and 61.2 ml/minute/1.73 m2, respectively (p = 0.003). There were significant differences in eGFR decline from baseline and de novo chronic kidney disease (CKD stage ≥ III) among groups, with PN followed by RN group showing the worst functional outcomes (all p <  0.05). Moreover, sequential PN subgroup in bilateral RCC showed significantly higher rate of de novo CKD than unilateral RCC group (13.8% vs. 6.9%, p = 0.016). On multivariate analysis, hypertension (p = 0.010) and surgery sequence (PN followed by RN, p <  0.001) were significant predictors of de novo CKD., Conclusions: The surgery sequence should be prudently determined in bilateral renal tumors. PN followed by RN showed a negative impact on renal functional preservation. Nephron-sparing surgery should be considered for all amenable bilateral RCCs.

The kidney plays a major role to maintain the constancy of the "milieu intérieur" by adjusting the urinary excretion of water and solutes to the requirement of the body balance. This function is coordinated with elimination of waste products generated among others by the catabolism of proteins and nucleic acids. To cope with these two major functions, the human kidneys generate each day about 180 L of ultrafiltrate from plasma and reabsorbs the vast majority of filtered water and solutes to excrete daily about one-two liter(s) of urine containing concentrations of sodium, potassium and chloride ranging from 20 to 200 mM. The final adjustment of urine composition is finely tuned along the aldosterone-sensitive distal nephron (ASDN) which includes the distal convoluted tubule and the collecting system (connecting tubule and collecting duct). Sodium reabsorption is predominant along the distal tubule if potassium must be spared, or along the collecting system when large amounts of potassium must be secreted. Nephrotic syndrome is characterized by heavy proteinuria consecutive to a glomerular injury, associated with renal sodium and water retention taking initially place along ASDN and leading to edema., (© 2021 médecine/sciences – Inserm.)

Intrauterine growth restriction (IUGR) is, in general, accompanied by a reduction of the nephron number, which increases the risk of hypertension and renal dysfunction. Studies have revealed that ouabain can partially restore the number of nephrons during IUGR. However, there is limited information regarding the melioration of nephric structure and function. We used maternal malnutrition to induce an IUGR model in rats. Subsequently, we used a mini-pump to administer ouabain to IUGR rats during pregnancy. Male offspring were divided randomly into two groups. One group was fed a normal diet, whereas the other was fed an isocaloric 8% high-salt diet. Maternal malnutrition led to a reduction in the birth weight and number of nephrons in offspring. At the end of a 40-week follow-up period, offspring from the IUGR group had high blood pressure and abnormal excretion of urinary protein; these parameters were exacerbated in offspring fed a high-salt diet. However, ouabain administration during pregnancy could partially restore the number of nephrons in IUGR offspring, normalize blood pressure, and reduce urinary protein excretion, even when challenged with a high-salt diet. Pathology findings revealed that IUGR, particularly following feeding of a high-salt diet, damaged the ultrastructure of glomeruli, but these harmful effects were ameliorated in offspring treated with ouabain. Collectively, our data suggest that ouabain could rescue nephrogenesis in IUGR newborns and protect (at least in part) the structure and function of the kidney during adulthood even when encountering unfavorable environmental challenges in subsequent life.

Alcohol during pregnancy can impair fetal development and result in offspring with neurodevelopmental deficits. Less is known about how low to moderate alcohol exposure can affect other organs, such as the kidney. Here, the effects of moderate ethanol exposure throughout pregnancy on kidney development were examined using a rat model. Rats were fed a liquid diet containing 6% ethanol (vol/vol) or control (0% ethanol) throughout pregnancy. Kidneys were collected at embryonic day (E) 20 or postnatal day (PN) 30 and total glomerular (nephron) number determined using unbiased stereology. Kidney function was examined in offspring at 8 and 19 months. At E20, fetuses exposed to ethanol had fewer nephrons with increased apoptosis. Alcohol exposure caused kidney dysregulation of pro- (Bax) and anti- (Bcl-2) apoptotic factors, and reduced expression of the cell proliferation marker, Ki67. Prenatal alcohol decreased expression of Gdnf and Tgfb1, important regulators of branching morphogenesis, in male fetuses. At PN30, kidney volume and nephron number were lower in offspring exposed to prenatal alcohol. Urine flow and osmolality were normal in offspring exposed to alcohol however sodium excretion tended to be lower in females prenatally exposed to alcohol. Findings suggest exposure to moderate levels of alcohol during pregnancy results in impaired kidney development and leads to a permanent nephron deficit. Although the impact on adult kidney function was relatively minor, these data highlight that even at moderate levels, alcohol consumption during pregnancy can have deleterious long-term outcomes and should be avoided., (© 2020 American Association for Anatomy.)

Nephron number in humans varies up to 13-fold, likely reflecting the impact of multiple factors on kidney development, including inherited body size and ethnicity, as well as maternal health and nutrition, fetal exposure to gestational diabetes or preeclampsia and other environmental factors, which may potentially be modifiable. Such conditions predispose to low or high offspring birth weight, growth restriction or preterm birth, which have all been associated with increased risks of higher blood pressures and/or kidney dysfunction in later life. Low birth weight, preterm birth, and intrauterine growth restriction are associated with reduced nephron numbers. Humans with hypertension and chronic kidney disease tend to have fewer nephrons than their counterparts with normal blood pressures or kidney function. A developmentally programmed reduction in nephron number therefore enhances an individual's susceptibility to hypertension and kidney disease in later life. A low nephron number at birth may not lead to kidney dysfunction alone except when severe, but in the face of superimposed acute or chronic kidney injury, a kidney endowed with fewer nephrons may be less able to adapt, and overt kidney disease may develop. Given that millions of babies are born either too small, too big or too soon each year, the population impact of altered renal programming is likely to be significant. Many gestational exposures are modifiable, therefore urgent attention is required to implement public health measures to optimize maternal, fetal, and child health, to prevent or mitigate the consequences of developmental programming, to improve the health future generations., (© 2019 American Association for Anatomy.)

Kidney regeneration could be classified into 2 groups: kidney generation and kidney repair. We have attempted in vivo nephron generation for kidney repair, as a therapy for chronic renal failure (CRF), by exploiting cellular interactions via conditioned media. In the previous report, we demonstrated the generation of rich nephrons in rat intact kidney cortices through percapsular injection of mesenchymal stem cell (MSC)-differentiated tubular epithelial cells (TECs) after pretreatment of 3-dimensional culture using a small amount of gel complex and condensed medium. In this study, to verify the amelioration of serum creatinine (sCr) levels by regenerated nephrons in rats with CRF, we first created damaged kidneys through systemic administration of adriamycin, and implanted the pretreated MSC-differentiated TECs into unilateral kidney cortices 2 weeks after adriamycin administration (A-2W, that is I-0W). After recovery of acute kidney injury, the control rats without cell implantation showed re-exacerbation of sCr levels, resulting in death within A-12W. Alternatively, the cell-implanted rats had a formation of mature nephrons in I-3W, and showed significant amelioration of sCr levels in I-7W. As a result, these rats could live until euthanization in I-12W or I-16W, indicating the utility of cell injection therapy into a kidney (K-CIT) for CRF. We expect that our K-CIT or the refined methods will be applied to patients with CRF., Competing Interests: Declaration of competing interest None, (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Seven theories address the evolution of secondary hyperparathyroidism (SHPT) as chronic kidney disease (CKD) progresses. The tradeoff-in-the-nephron hypothesis states that the plasma parathyroid hormone ([PTH]) concentration rises because an increased phosphate concentration in the cortical distal nephron ([P] CDN ) reduces the ionized calcium concentration in that segment. In the present study, we compared this hypothesis to its predecessors., Materials and Methods: We studied 30 patients with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m 2 (mean 29.5). To examine historic theories, we performed regressions of [PTH] on plasma concentrations of ionized calcium, phosphorus, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and fibroblast growth factor 23, and on calcium excreted per volume of filtrate (E Ca /C cr ). To assess the tradeoff-in-the-nephron hypothesis, we examined regressions of [PTH] on 100/eGFR and phosphorus excreted per volume of filtrate (E P /C cr )., Results: Regressions pertinent to historic theories yielded significant direct relationships between [PTH] and both E Ca /C cr and [FGF23], but neither association supported the theory to which it pertained. [PTH] varied directly with 100/eGFR and with E P /C cr , a surrogate for [P] CDN . E P /C cr correlated strongly with 100/eGFR., Conclusions: The only theory of SHPT that our data support is the tradeoff-in-the-nephron hypothesis. Other theories are not supported.

Exposure to a sub-optimal environment in the womb can result in poor fetal growth and impair the normal development of organs. The kidney, specifically the process of nephrogenesis, has been shown to be impacted by many common pregnancy exposures including an inadequate diet, poor placental function, maternal stress as well as maternal smoking and alcohol consumption. This can result in offspring being born with a reduced nephron endowment, which places these individuals at increased risk of hypertension and chronic kidney disease (CKD). Of recent interest is whether this disease risk can be passed on to subsequent generations and, if so, what are the mechanisms and pathways involved. In this review, we highlight the growing body of evidence that a low birth weight and hypertension, which are both major risk factors for cardiovascular and CKD, can be transmitted across generations. However, as yet there is little data as to whether a low nephron endowment contributes to this disease transmission. The emerging data suggests transmission can occur both through both the maternal and paternal lines, which likely involves epigenetic mechanisms such chromatin remodelling (DNA methylation and histone modification) and non-coding RNA modifications. In addition, females who were born small and/or have a low nephron endowment are at an increased risk for pregnancy complications, which can influence the growth and development of the next generation. Future animal studies in this area should include examining nephron endowment across multiple generations and determining adult renal function. Clinically, long term follow-up studies of large birth cohorts need to be undertaken to more clearly determine the impact a sub-optimal environment in one generation has on the health outcomes in the second, and subsequent, generation., (Copyright © 2018. Published by Elsevier Ltd.)

Owing to its rarity and severe nature, the treatment for generalized pseudohypoaldosteronism type 1 (PHA1), a genetic disorder in the epithelial sodium channel (ENaC), is exclusively experience-based. In particular, the usefulness of dietary potassium restriction in PHA1 remains unclear with the absence of theoretical background to elucidate its utility. First, we demonstrated the effect of potassium restriction in a 13-month-old patient with ENaC γ-subunit gene mutations via a retrospective chart review; reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity. The serum potassium level decreased from 5.6 to 4.5 mEq/L. Next, we attempted to elucidate the pathophysiological basis of the usefulness of potassium restriction, leveraged by the increased knowledge regarding the roles of with-no-lysine kinases (WNKs) in the distal nephron. When potassium is restricted, the WNK signal will turn "on" in the distal nephron via reduction in the intracellular chloride level. Consequently, the sodium reabsorption from the Na + Cl - cotransporter (NCC) in the distal convoluted tubule and possibly from pendrin in the β-intercalated cell will increase. Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct. In conclusion, dietary potassium restriction is one of the indispensable treatments for generalized PHA1.

Our recently reported phase III trial demonstrated that patients undergoing nephron-sparing surgery (NSS) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m 2 who received mannitol had no improvement in renal function at 6 mo compared with those who received placebo. Some authors have suggested that benefit is restricted to subgroups, such as those with comorbidities. We assessed whether preoperative eGFR, or other patient and surgical factors modified the effect of mannitol on postoperative outcomes at 6 mo and with extended follow-up. We also assessed whether mannitol was associated with differences in long-term GFR years after surgery. No significant difference between the mannitol or placebo groups (mean eGFR difference: 1.4; 95% confidence interval: -2.6, 5.3; p = 0.5) was found in the 134 patients with known eGFR at 3 yr after NSS. At both 6 mo and 3 yr, the effect of mannitol was not significantly modified by patient or surgical factors including preoperative eGFR. In summary, we validated our original trial conclusions by finding that intraoperative use of mannitol does not improve either short- or long-term renal function in patients undergoing NSS. Specifically, there is no evidence that comorbidities, including lower preoperative eGFR, modify the effect of mannitol. PATIENT SUMMARY: Use of mannitol at the time of partial nephrectomy does not improve either short- or long-term renal function even in patients with comorbidities, including lower preoperative renal function. The routine use of intraoperative mannitol should be discontinued., (Copyright © 2019. Published by Elsevier B.V.)

Purpose of Review: Serum creatinine and urine output continue to be the mainstays of diagnosis of acute kidney injury, though both of these measures have significant limitations, especially in acutely hospitalized patients. Biomarkers in both blood and urine have been studied extensively in the research setting and are on the verge of clinical practice to improve diagnosis of AKI., Recent Findings: Blood and urine biomarkers can be localized to specific areas or functions within the nephron. Biomarkers can help to characterize glomerular or tubular function; glomerular, tubular, or interstitial injury; inflammation; or repair. Further, biomarkers can improve diagnosis of AKI in various clinical settings including acute interstitial nephritis, acute tubular injury, and hepatorenal syndrome, and cardiorenal syndrome., Summary: Biomarkers are becoming more prevalent in both research and getting close to clinical use. Both blood and urine biomarkers can help to localize impairment in nephron health by either location or function within the nephron and among various causes of AKI.

Objective: To evaluate the significance of sonographic perinephric fluid collection on the emergent management of patients with acute urinary stone obstruction., Methods: We conducted a prospective study with retrospective analysis. Since January 2016 through July 2017, patients admitted to our tertiary hospital's emergency department (ED) with suspected symptomatic urinary stones underwent ultrasound evaluation. Images were prospectively interpreted by experienced radiologist who analyzed each case for the following imaging features: hydronephrosis, perinephric fluid and urethral stone identification. The presence and measurements of perinephric fluid were re-evaluated by second radiologist who was blinded for the first reader's measurements. Retrospective analysis was conducted to evaluate for an association between perinephric fluid collection and the following outcome variables: need for analgesics, the number of doses of analgesics and the amount of morphine (mg) in the ED, elevation of creatinine levels, hospitalization and need for urological interventions., Results: The need for analgesics, the number of doses of analgesics and the amount of morphine were significantly associated with the presence of perinephric fluid (p < 0.05). The odds ratio for the need for analgesics was 3.8 in the presence of any perinephric fluid, and 8.9 in the presence of moderate/severe perinephric fluid. No other patient outcome variables were found to be significantly associated with the presence of perinephric fluid (p > 0.05)., Conclusions: This study shows a correlation between sonographic evidence of perinephric fluid and more severe pain. Therefore, an emergency physician can consider the evidence of perinephric fluid, in acute urethral stone obstruction, a predictor for more severe pain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A deficit or loss in the number of nephrons, the functional unit of the kidney, can induce compensatory growth and hyperfunction of remaining nephrons. An increase in single nephron glomerular filtration rate (SNGFR) aims to compensate but may be deleterious in the long term. The increase in SNGFR is determined by the dynamics of nephron loss, total remaining GFR, the body's excretory demand, and the functional capacity to sustain single nephron hyperfunction.

Maternal insufficiency during fetal development can have long-lasting effects on the offspring, most notably on nephron endowment. In polycystic kidney disease (PKD), variability in severity of disease is observed and maternal environment may be a modifying factor. In this study, we first established that in a rodent model of PKD, the Lewis polycystic kidney (LPK) rat's nephron numbers are 25% lower compared with wildtype animals. We then investigated the effects of prenatal and postnatal maternal environment on phenotype and nephron number. LPK pups born from and raised by homozygous LPK dams (control) were compared with LPK pups cross-fostered onto heterozygous LPK dams to improve postnatal environment; with LPK pups born from and raised by heterozygous LPK dams to improve both prenatal and postnatal environment and with LPK pups born from and raised by Wistar Kyoto-LPK heterozygous dams to improve both prenatal and postnatal environment on a different genetic background. Improvement in both prenatal and postnatal environment improved postnatal growth, renal function and reduced blood pressure, most notably in animals with different genetic background. Animals with improved postnatal environment only showed improved growth and blood pressure, but to a lesser extent. All intervention groups showed increased nephron number compared with control LPK. In summary, prenatal and postnatal environment had significant effect in delaying progression and reducing severity of PKD, including nephron endowment.

Purpose of Review: Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF., Recent Findings: The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose. Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM), a plasma cell cancer, is associated with many health challenges, including damage to the kidney by tubulointerstitial fibrosis. We develop a mathematical model which captures the qualitative behavior of the cell and protein populations involved. Specifically, we model the interaction between cells in the proximal tubule of the kidney, free light chains, renal fibroblasts, and myeloma cells. We analyze the model for steady-state solutions to find a mathematically and biologically relevant stable steady-state solution. This foundational model provides a representation of dynamics between key populations in tubulointerstitial fibrosis that demonstrates how these populations interact to affect patient prognosis in patients with MM and renal impairment.

Background: Nephron-sparing surgery (NSS) remains gold standard for the treatment of localised renal cell cancer (RCC), even in case of a normal contralateral kidney. Compared to radical nephrectomy, kidney failure and cardiovascular events are less frequent with NSS. However, the effects of different surgical approaches and of zero ischaemia on the postoperative reduction in renal function remain controversial. We aimed to investigate the relative short- and long-term changes in estimated glomerular filtration rate (eGFR) after ischaemic or zero-ischaemic open (ONSS) and laparoscopic NSS (LNSS) for RCC, and to analyse prognostic factors for postoperative acute kidney injury (AKI) and chronic kidney disease (CKD) stage ≥3., Methods: Data of 444 patients (211 LNSS, 233 ONSS), including 57 zero-ischaemic cases, were retrospectively analysed. Multiple regression models were used to predict relative changes in renal function. Natural cubic splines were used to demonstrate the association between ischaemia time (IT) and relative changes in renal function., Results: IT was identified as significant risk factor for short-term relative changes in eGFR (ß = - 0.27) and development of AKI (OR, 1.02), but no effect was found on long-term relative changes in eGFR. Natural cubic splines revealed that IT had a greater effect on patients with baseline eGFR categories ≥G3 concerning short-term decrease in renal function and development of AKI. Unlike LNSS, ONSS was significantly associated with short-term decrease in renal function (ß = - 13.48) and development of AKI (OR, 3.87). Tumour diameter was associated with long-term decrease in renal function (ß = - 1.76), whereas baseline eGFR was a prognostic factor for both short- (ß = - 0.20) and long-term (ß = - 0.29) relative changes in eGFR and the development of CKD stage ≥3 (OR, 0.89)., Conclusions: IT is a significant risk factor for AKI. The short-term effect of IT is not always linear, and the impact also depends on baseline eGFR. Unlike LNSS, ONSS is associated with the development of AKI. Our findings are helpful for surgical planning, and suggest either the application of a clampless NSS technique or at least the shortest possible IT to reduce the risk of short-time impairment of the renal function, which might prevent AKI, particularly regarding patients with baseline eGFR category ≥G3.

Background: If loss of functioning nephrons predisposes to glomerular barotrauma (a "remnant nephron" effect), then glomerular permeability should increase as glomerular filtration rate (GFR) falls, as is observed in animal models of nephron loss., Methods: Changes in net renal protein permeability, defined as proteinuria or albuminuria per mL/min of GFR, were measured in the setting of nephron loss due to kidney donation (Assessing Long Term Outcomes in Living Kidney Donors cohort) or progressive chronic kidney disease (CKD; Modification of Diet in Renal Disease [MDRD], African American Study of Kidney Disease [AASK], and Chronic Renal insufficiency Cohort [CRIC] studies)., Results: Following kidney donation, renal albumin permeability increased by 31% from predonation levels (p < 0.001). With progression of CKD, a 50% loss of residual GFR was accompanied by increases in proteinuria per mL/min GFR of 1.8-, 2.1-, and 1.6-fold in the MDRD, AASK, and CRIC cohorts, respectively (p < 0.001 for all), independent of changes in systolic blood pressure and ACEi/ARB use. A 70% reduction in GFR was associated with permeability increases of 3.1-, 4.4-, and 2.6-fold in the same cohorts. Among MDRD participants with progression of nonglomerular primary disease, the 75th percentile of final permeability was 141 mg/24 h proteinuria per mL/min GFR. This degree of permeability would have resulted in nephrotic range proteinuria had it been present at the baseline mean GFR of 40 mL/min, implying the development of de novo glomerular pathology as GFR fell. Increasing permeability also accompanied CKD progression in participants with nephrotic syndrome at baseline. Consequently, these participants had little improvement in 24 h proteinuria or serum albumin, despite substantial loss of functioning nephron mass across which the protein leak occurred. In the absence of a fall in GFR, there was no increase in permeability in any cohort., Conclusion: Nephron loss is accompanied by an increase in renal protein permeability, even in the absence of a primary glomerular disease. This is consistent with a remnant nephron effect in human CKD., (© 2019 S. Karger AG, Basel.)

To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression. Lethality by ~3 wk, however, limits the usefulness of this model, so we developed a kidney-specific Kir4.1 "knockdown" mouse (ksKD) using a cadherin 16 promoter and Cre-loxP methodology. These mice appeared normal and survived to adulthood. Kir4.1 protein expression was decreased ~50% vs. wild-type (WT) mice by immunoblotting, and immunofluorescence showed moderately reduced Kir4.1 staining in distal convoluted tubule that was minimal or absent in connecting tubule and cortical collecting duct. Under control conditions, the ksKD mice showed metabolic alkalosis and relative hypercalcemia but were normokalemic and mildly hypermagnesemic despite decreased NCC expression. In addition, the mice had a severe urinary concentrating defect associated with hypernatremia, enlarged kidneys with tubulocystic dilations, and reduced aquaporin-3 expression. On a K/Mg-free diet for 1 wk, however, ksKD mice showed marked hypokalemia (serum K: 1.5 ± 0.1 vs. 3.0 ± 0.1 mEq/l for WT), which was associated with renal K wasting (transtubular K gradient: 11.4 ± 0.8 vs. 1.6 ± 0.4 in WT). Phosphorylated-NCC expression increased in WT but not ksKD mice on the K/Mg-free diet, suggesting that loss of NCC adaptation underlies the hypokalemia. In conclusion, even modest reduction in Kir4.1 expression results in impaired K conservation, which appears to be mediated by reduced expression of activated NCC.

Determining the future state of individual patients, with regard to the susceptibility to life-threatening condition is a crucial problem in the public health. Chronic Kidney Disease (CKD) is a perilous disease, which is characterized by gradual loss of kidney function. This paper presents a set of mathematical models for CKD by applying both deterministic and stochastic approaches. Specifically, hypertension and stress are considered as the main causes of damaging and removing of nephrons thereby reducing the Glomerular Filtration Rate (GFR), which leads to irreparable damages to the kidney function and may result in renal failure, or even kidney loss. This paper analyzes the equilibria for both deterministic and stochastic models. In this regard, mathematical theorems related to stability and stochastic stability of the models are provided. The other important issue, which is discussed in the presented work, is the uncertainty problem for stochastic models. We have used simulations in MATLAB to calculate the uncertainty of the stochastic models. In addition, we have provided a framework for the future prediction of proposed models in specific cases. Finally, the models and the theoretical results are verified in application by applying them to the real clinical data., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Kidney regeneration from pluripotent stem cells is receiving a lot of attention because limited treatments are currently available for chronic kidney disease (CKD). It has been shown that uremic state in CKD is toxic to somatic stem/progenitor cells, such as endothelial progenitor and mesenchymal stem cells, affecting their differentiation and angiogenic potential. Recent studies reported that specific abnormalities caused by the non-inherited disease are often retained in induced pluripotent stem cell (iPSC)-derived products obtained from patients. Thus, it is indispensable to first assess whether iPSCs derived from patients with CKD due to non-inherited disease (CKD-iPSCs) have the ability to generate kidneys. In this study, we generated iPSCs from patients undergoing haemodialysis due to diabetes nephropathy and glomerulonephritis (HD-iPSCs) as representatives of CKD-iPSCs or from healthy controls (HC-iPSCs). HD-iPSCs differentiated into nephron progenitor cells (NPCs) with similar efficiency to HC-iPSCs. Additionally, HD-iPSC-derived NPCs expressed comparable levels of NPC markers and differentiated into vascularised glomeruli upon transplantation into mice, as HC-iPSC-derived NPCs. Our results indicate the potential of HD-iPSCs as a feasible cell source for kidney regeneration. This is the first study paving the way for CKD patient-stem cell-derived kidney regeneration, emphasising the potential of CKD-iPSCs.

Our knowledge on sodium and water homeostasis and regulation continues to evolve. A considerable amount of new information in this area has emerged in recent years. This review summarizes existing and new literature and discusses complex multi-organ effects of high-salt and low-water intake and role of arginine vasopressin in this process, as well as the potential clinical significance of non-osmotic sodium storage pool and rhythmicity of urine sodium excretion. It has become clear that sodium and water dysregulation can exert profound effects on kidney and vascular health, far greater than previously recognized. Maladaptation to a combined high-salt and low-water intake can be linked to the growing epidemic of hypertension and chronic kidney disease., (© 2018 The Authors Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

It is well known that the nephron endowment of healthy subjects is highly variable and that individual nephron mass has potentially important implications both in health and disease. However, nephron count is technically impossible in living subjects. Based on the observation of an increase in serum creatinine (sCr) in otherwise healthy newborns with solitary kidney during the physiological perinatal dehydration, we hypothesized that perinatal sCr might be helpful in identifying healthy subjects with a reduced nephron mass. In the framework of a study on blood pressure in babies (NeoNeph), sCr of normal Caucasian neonates was determined 48-96 h after birth and their association with a family history of arterial hypertension (AH) was analyzed. SCr was determined in 182 normal newborns (90 males) at a mean of 61 ± 8 h after birth (range 46-82). Newborns with paternal AH had a higher mean sCr (0.97 + 0.28 mg/dL) then newborns without paternal AH (0.73 + 0.28 mg/dL; p = 0.006). No differences in mean sCr were found in relation with mother or grandparent's history of AH., Conclusion: The association between parental AH and high sCr during perinatal dehydration supports the hypothesis that the latter is a promising tool for identifying normal subjects with a reduced nephron mass with potential important implications in prevention and in understanding the individual outcome of renal and extrarenal diseases (including AH). What is Known: • Nephron endowment of healthy subjects is highly variable and individual nephron mass has potentially important implications both in health and disease however nephron count is not feasible in living subjects. What is New: • Serum creatinine during perinatal dehydration is a possible biomarker for identifying normal subjects with a reduced nephron mass.

Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of Dis3l2 -null nephron progenitor cells, a potential cell of origin of Wilms tumors, reveals up-regulation of Igf2 , a growth-promoting gene strongly associated with Wilms tumorigenesis. These findings nominate a new potential mechanism underlying the pathology associated with DIS3L2 deficiency., (© 2018 Hunter et al.; Published by Cold Spring Harbor Laboratory Press.)

In diseases of many parenchymatous organs, heterogeneous deterioration of individual functional units determines the clinical prognosis. However, the molecular characterization at the level of such individual subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Proteinuric glomerular kidney diseases are frequent and assorted diseases affecting a fraction of glomeruli and their draining tubules to variable extents, and for which no specific treatment exists. Here, we developed and applied a mass spectrometry-based methodology to investigate heterogeneity of proteomes from individually isolated nephron segments from mice with proteinuric kidney disease. In single glomeruli from two different mouse models of sclerotic glomerular disease, we identified a coherent protein expression module consisting of extracellular matrix protein deposition (reflecting glomerular sclerosis), glomerular albumin (reflecting proteinuria) and LAMP1, a lysosomal protein. This module was associated with a loss of podocyte marker proteins while genetic ablation of LAMP1-correlated lysosomal proteases could ameliorate glomerular damage in vivo. Furthermore, proteomic analyses of individual glomeruli from patients with genetic sclerotic and non-sclerotic proteinuric diseases revealed increased abundance of lysosomal proteins, in combination with a decreased abundance of mutated gene products. Thus, altered protein homeostasis (proteostasis) is a conserved key mechanism in proteinuric kidney diseases. Moreover, our technology can capture intra-individual variability in diseases of the kidney and other tissues at a sub-biopsy scale., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Autosomal dominant mutations in cullin-3 ( Cul3) cause the most severe form of familial hyperkalemic hypertension (FHHt). Cul3 mutations cause skipping of exon 9, which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the cullin-RING ubiquitin ligase family that mediates ubiquitination and thus degradation of cellular proteins, including with-no-lysine [K] kinases (WNKs). In CUL3-∆9-mediated FHHt, proteasomal degradation of WNKs is abrogated, leading to overactivation of the WNK targets sterile 20/SPS-1 related proline/alanine-rich kinase and oxidative stress-response kinase-1, which directly phosphorylate and activate the thiazide-sensitive Na + -Cl - cotransporter. Several groups have suggested different mechanisms by which CUL3-∆9 causes FHHt. The majority of these are derived from in vitro data, but recently the Kurz group (Schumacher FR, Siew K, Zhang J, Johnson C, Wood N, Cleary SE, Al Maskari RS, Ferryman JT, Hardege I, Figg NL, Enchev R, Knebel A, O'Shaughnessy KM, Kurz T. EMBO Mol Med 7: 1285-1306, 2015) described the first mouse model of CUL3-∆9-mediated FHHt. Analysis of this model suggested that CUL3-∆9 is degraded in vivo, and thus Cul3 mutations cause FHHt by inducing haploinsufficiency. We recently directly tested this model but found that other dominant effects of CUL3-∆9 must contribute to the development of FHHt. In this review, we focus on our current knowledge of CUL3-∆9 action gained from in vitro and in vivo models that may help unravel this complex problem.

Introduction: Partial nephrectomy (PN) is the gold standard treatment for renal cell carcinomas under 4cm. No robust data exists to recommend PN for tumours>7cm (cT2). The objective of this work is to evaluate the results of PN for cT2 tumours., Patients and Methods: All patients who underwent PN or radical nephrectomy (RN) for cT2 tumours between 2000 and 2013 at our institution have been included. Patient demographics, postoperative data including renal function, morbidity, mortality and oncologic outcomes were reviewed retrospectively and compared using χ 2 test, Mann-Whitney test, Kaplan-Meier method and log rank test., Results: We included 130 patients, 49 (38%) in the PN group and 81 (62%) in the RN group, with a median follow-up of 42 months [19-69]. Variation of postoperative renal function at day 5 and last recorded value was significantly different between the groups (P=0.03 and P<0.001). The PN group had a significantly higher complication rate as compared with RN group (37% versus 14%, P=0.002). There were no significant differences between the two groups for overall, recurrence free and specific survival (P=0.55, P=0.55, P=0.24, respectively). In univariate analysis, the type of surgery (PN versus RN) was not associated with a significant difference of oncologic outcome (margins, survival)., Conclusion: PN can be offered for cT2 tumours with oncological outcomes similar to RN. Despite an increased morbidity, it remains acceptable with the demonstrated advantage of preservation of renal function., Level of Evidence: 4., (Copyright © 2018. Published by Elsevier Masson SAS.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors enhance urinary glucose, Na + and fluid excretion, and lower hyperglycemia in diabetes by targeting Na + and glucose reabsorption along the proximal convoluted tubule. A goal of this study was to predict the effects of SGLT2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease. To that end, we employed computational rat kidney models to explore how SGLT2 inhibition affects renal solute transport and metabolism when nephron populations are normal or reduced. Model simulations suggested that in a nondiabetic rat, acute and chronic SGLT2 inhibition induces glucosuria, diuresis, natriuresis, and kaliuresis. Those effects were stronger with chronic SGLT2 inhibition (due to SGLT1 downregulation) and tempered by nephron loss. In a diabetic rat with normal nephron number, acute SGLT2 inhibition similarly elevated urine fluid, Na + , and K + excretion, whereas the urinary excretory effects of chronic SGLT2 inhibition were attenuated in proportion to its plasma glucose level lowering effect. Nephron loss in a diabetic kidney was predicted to lower the glucosuric and blood glucose-reducing effect of chronic SGLT2 inhibition, but due to the high luminal glucose delivery in the remaining hyperfiltering nephrons, nephron loss enhanced proximal tubular paracellular Na + secretion, thereby augmenting the natriuretic, diuretic, and kaliuretic effects. A proposed shift in oxygen-consuming active transport to the outer medulla, which may simulate systemic hypoxia and enhance erythropoiesis, was also preserved with nephron loss. These effects may contribute to the protective effects of SGLT2 inhibitors on blood pressure and heart failure observed in diabetic patients with chronic kidney diseases.

Background: Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney., Methods/design: This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group., Discussion: In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney., Trial Registration: Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973 . Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016.

We summarize the current understanding of the physiology of the renal handling of potassium (K + ), and present an integrative view of the renal response to K + depletion caused by dietary K + restriction. This renal response involves contributions from different nephron segments, and aims to diminish the rate of excretion of K + as a result of: decreasing the rate of electrogenic (and increasing the rate of electroneutral) reabsorption of sodium in the aldosterone-sensitive distal nephron (ASDN), decreasing the abundance of renal outer medullary K + channels in the luminal membrane of principal cells in the ASDN, decreasing the flow rate in the ASDN, and increasing the reabsorption of K + in the cortical and medullary collecting ducts. The implications of this physiology for the association between K + depletion and hypertension, and K + depletion and formation of calcium kidney stones are discussed., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) is defined by persistent urine abnormalities, structural abnormalities or impaired excretory renal function suggestive of a loss of functional nephrons. The majority of patients with CKD are at risk of accelerated cardiovascular disease and death. For those who progress to end-stage renal disease, the limited accessibility to renal replacement therapy is a problem in many parts of the world. Risk factors for the development and progression of CKD include low nephron number at birth, nephron loss due to increasing age and acute or chronic kidney injuries caused by toxic exposures or diseases (for example, obesity and type 2 diabetes mellitus). The management of patients with CKD is focused on early detection or prevention, treatment of the underlying cause (if possible) to curb progression and attention to secondary processes that contribute to ongoing nephron loss. Blood pressure control, inhibition of the renin-angiotensin system and disease-specific interventions are the cornerstones of therapy. CKD complications such as anaemia, metabolic acidosis and secondary hyperparathyroidism affect cardiovascular health and quality of life, and require diagnosis and treatment.

Background: Despite compensatory hyperfiltration in remaining nephrons following donor nephrectomy, some donors show impaired renal adaptation and low estimated glomerular filtration rate (eGFR). We investigated the factors predicting early renal adaptation after nephrectomy and identified kidney donors at risk of inadequate renal adaptation., Methods: A total of 265 living kidney donors from 2010 to 2013 were retrospectively analyzed. Renal function was serially followed for 6 months after the operation. Regression analyses were performed to identify the independent predictors of low eGFR (eGFR <60 mL/min/1.73 m 2 ) and impaired renal adaptation (%Modification of Diet in Renal Disease [MDRD] <66% of baseline eGFR)., Results: A total of 148 donors belonged to the low eGFR group, and changes in eGFR (ΔeGFR) at postoperative (PO) 1 day and 1 month were identified as independent predictors of low eGFR. Impaired renal adaptation was related to age, ΔeGFR PO 2-3 days, and ΔeGFR PO 1 month. Early renal adaptation was associated with age, male gender, and residual kidney computerized tomography angiography (CTA) volume. The best sensitivity and specificity were obtained with a cutoff value of ΔeGFR 31 at PO 1 day and 1 month for predicting low eGFR and with a value of ΔeGFR 27 at PO 2-3 days and 1 month for predicting impaired renal adaptation., Conclusions: Our study showed that the degree of early renal adaptation determines subsequent renal function in kidney donors. Closer monitoring and management may be required in old or male donors with small residual CTA kidney volume as well as donors with persistent ΔeGFR >27 within 1 month of nephrectomy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Understanding the location and action of nephron transporters and channels is important to the understanding of renal function. As each region of the nephron is unique in its inclusion of specific transporters and channels, mapping of the nephron is an effective first step in understanding overall nephron processing. We describe a small-group, active-learning exercise that facilitates students' ability to understand renal processing within each region of the nephron., Methods: Following an overview lecture on renal transporters and channels, small groups of students worked cooperatively to map the nephron. This 2-hour, collaborative exercise was developed to reinforce key concepts in renal processing of ions and nutrients and, at the same time, utilize effective learning strategies. Learning strategies incorporated in this exercise include small-group collaboration, peer teaching, retrieval practice using an audience response system, and elaboration through discussion., Results: Written examination was used to assess student understanding. Students demonstrated higher performance on a subset of questions related to this learning activity compared to the overall exam. Highly positive feedback was provided by a convenience sample of students completing an anonymous survey., Discussion: This nephron-mapping exercise was an effective means to promote synthesis and analysis of lecture content and engage students in methods that enhance learning., Competing Interests: None to report.

Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive (n = 3; group A) or negative (n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs., (© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral resistance. It is commonly accepted that increased renal sodium handling and plasma volume expansion are necessary factors for the development of salt-induced hypertension. The epithelial sodium channel (ENaC) is a trimeric ion channel expressed in the distal nephron that plays a critical role in the regulation of sodium reabsorption in both normal and pathological conditions. In this mini-review, we summarize recent studies investigating the role of ENaC in the development of salt-sensitive hypertension. On the basis of experimental data obtained from the Dahl salt-sensitive rats, we and others have demonstrated that abnormal ENaC activation in response to a dietary NaCl load contributes to the development of high blood pressure in this model. The role of different humoral factors, such as the components of the renin-angiotensin-aldosterone system, members of the epidermal growth factors family, arginine vasopressin, and oxidative stress mediating the effects of dietary salt on ENaC are discussed in this review to highlight future research directions and to determine potential molecular targets for drug development., (Copyright © 2017 the American Physiological Society.)

Preterm birth occurs in approximately 10% of all births worldwide. Preterm infants have reduced nephron numbers at birth in proportion to gestational age, and are at increased risk of neonatal acute kidney injury as well as higher blood pressure, proteinuria, and chronic kidney disease later in life. Rapid catch-up growth in preterm infants, especially if resulting in obesity, is a risk factor for end-stage kidney disease among children with proteinuric renal disease. Preterm birth, however, is a risk factor not only for the infant because mothers who deliver preterm have an increased risk of having subsequent preterm deliveries as well as hypertension, cardiovascular disease, and renal disease later in life. Preterm birth in a female infant is also a risk factor for her future risk of having a preterm delivery, gestational hypertension, and gestational diabetes, which in turn may impact the development of fetal kidneys and the offspring's risk of hypertension and renal disease. This intergenerational programming cycle, therefore, perpetuates the risks and consequences of prematurity. Interruption of this cycle may be possible through optimization of maternal nutrition and health as well as careful antenatal care, which may in turn reduce the global burden of hypertension and renal disease in subsequent generations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Acute kidney injury affects ~70% of asphyxiated newborns, and increases their risk of developing chronic kidney disease later in life. Acute kidney injury is driven by renal oxygen deprivation during asphyxia, thus we hypothesized that creatine administered antenatally would protect the kidney from the long-term effects of birth asphyxia., Methods: Pregnant spiny mice were fed standard chow or chow supplemented with 5% creatine from 20-d gestation (midgestation). One day prior to term (37-d gestation), pups were delivered by caesarean or subjected to intrauterine asphyxia. Litters were allocated to one of two time-points. Kidneys were collected at 1 mo of age to estimate nephron number (stereology). Renal function (excretory profile and glomerular filtration rate) was measured at 3 mo of age, and kidneys then collected for assessment of glomerulosclerosis., Results: Compared with controls, at 1 mo of age male (but not female) birth-asphyxia offspring had 20% fewer nephrons (P < 0.05). At 3 mo of age male birth-asphyxia offspring had 31% lower glomerular filtration rate (P < 0.05) and greater glomerular collagen IV content (P < 0.01). Antenatal creatine prevented these renal injuries arising from birth asphyxia., Conclusion: Maternal creatine supplementation during pregnancy may be an effective prophylactic to prevent birth asphyxia induced acute kidney injury and the emergence of chronic kidney disease.

Obstructive acute renal failure is a heterogeneous entity as the pathophysiology of intratubular obstruction is quite different from upper tract obstruction. In the former case, tubules are dilated due to a high hydrostatic pressure whereas pressures are normal in urinary upper tract. In the latter case, a high pressure above the ureteral obstacle is responsible for dilated renal cavities leading to extrinsic compression with no or only few dilated tubules though high hydrostatic pressure are recorded within tubules. Obstruction within tubules may be related to crystal formation, exfoliated cells, cellular debris and/or protein gels altogether with cell proliferation, proliferating cells, and recruitment of inflammatory cells. Though fibrosis may develop, the occurrence of atubular glomeruli in several nephrons due to an initial loss of tubular patency highlights the critical importance of maintaining a fluid flow within tubules in order to avoid uncontrolled tubular cell proliferation. The onset of tubular obstruction in few tubules, especially in crystal nephropathy is underestimated especially in chronic kidney disease patients, thus suggesting that some macromolecular solubilizing factors may be potential relevant therapy to prevent (and/or reverse) chronic kidney disease progression or decrease acute renal failure sequelae., (Copyright © 2017 Association Société de néphrologie. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Renal involvement is a rare complication of β-thalassemia. Both tubular and glomerular dysfunction might occur in these patients. The aim of this study was to evaluate and compare kidney function in the major, intermedia, and minor variants of β-thalassemia., Materials and Methods: Renal tubular and glomerular function of 72 patients with β-thalassemia (25 major, 23 intermedia, and 24 minor) were evaluated. Patients older than 40 years and those with chronic kidney disease, diabetes mellitus, congestive heart failure, associated infections, congenital anomalies of the kidney and urinary tract were excluded. Blood and urine samples were collected electrolytes and markers of kidney function., Results: Mean age at the time of study was significantly higher in the minor group. The majority of patients with thalassemia major were males. Hematuria and pyuria occurred in 4% to 8% of the patients. Serum level of all variables were within normal limits, with no significant difference between the three groups. Glomerular filtration rate was nonsignificantly higher in the major and intermedia groups, compared to the minor variant. A significantly lower urine phosphorus and uric acid excretion was noted with the minor variant. Urine phosphorus and uric acid excretion increased more frequently in the major and intermedia groups., Conclusions: Tubular and glomerular functions appear to be well preserved in all variants of β-thalassemia.

The kidneys play a vital role in the excretion of waste products and the regulation of electrolytes, maintenance of acid-base balance, regulation of blood pressure, and production of several hormones. Any alteration in the structure of the nephron (basic functional unit of the kidney) can have a major impact on the kidney's ability to work efficiently. Progressive decline in kidney function can lead to serious illness and ultimately death if not treated by dialysis or transplantation. While there have been numerous studies that implicate lower nephron numbers as being an important factor in influencing susceptibility to developing hypertension and chronic kidney disease, a direct association has been difficult to establish because of three main limitations: 1 ) the large variation in nephron number observed in the human population; 2 ) no established reliable noninvasive methods to determine nephron complement; and 3 ) to date, nephron measurements have been done after death, which doesn't adequately account for potential loss of nephrons with age or disease. In this review, we will provide an overview of kidney structure/function, discuss the current literature for both humans and other species linking nephron deficiency and cardio-renal complications, as well as describe the major molecular signaling factors involved in nephrogenesis that modulate variation in nephron number. As more detailed knowledge about the molecular determinants of nephron development and the role of nephron endowment in the cardio-renal system is obtained, it will hopefully provide clinicians the ability to accurately identify people at risk to develop CKD/hypertension and lead to a shift in patient care from disease treatment to prevention., (Copyright © 2017 the American Physiological Society.)

Introduction: We evaluated whether nephron sparing surgery (NSS) combined with meticulous suturing of the cut stump under clamping with cooling is beneficial for oncological outcomes and also assessed the relationship between cold ischemia time and deterioration of renal function., Methods: One hundred and six patients with renal cell carcinoma (RCC) were subjected to this procedure. Oncological outcomes and renal function according to the estimated glomerular filtration rate (eGFR) and the tubular excretion rate on renoscintigraphy before and at 12 months after surgery were evaluated., Results: Cancer recurrences were observed in 2 patients with past history of RCC; however, no patient died of cancer. Renal function was evaluated depending on 4 different ischemia times. All groups did not show a remarkable decrease of renal function in terms of eGFR. Renoscintigraphy revealed the deterioration of the affected kidney in patients with >60 min ischemia., Conclusion: The renoprotective procedure of NSS provided maximum preservation of renal function until 60 min of cold ischemia time., (© 2017 S. Karger AG, Basel.)

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.

Background and Objectives: Hyperfiltration at the single-nephron level has been proposed as an early stage of kidney dysfunction of different origins. Evidence supporting this hypothesis in humans is lacking, because there is no method of measuring single-nephron GFR in humans. However, increased whole-kidney GFR in the same individual implies an increased single-nephron GFR, because the number of nephrons does not increase with age. We hypothesized that an increase in GFR would be associated with an increased albumin-to-creatinine ratio in a cohort of the general population., Design, Setting, Participants, & Measurements: We measured GFR by iohexol clearance at baseline in 2007-2009 and follow-up after 5.6 years in a representative sample of 1246 persons (aged 50-62 years) who were nondiabetic from the general population of Tromso, northern Norway. Participants were without cardiovascular disease, kidney disease, or diabetes at baseline. We investigated the association between change in GFR and change in albumin-to-creatinine ratio. Increased GFR was defined as a positive change in GFR (change in GFR>0 ml/min) from baseline to follow-up. An albumin-to-creatinine ratio >30 mg/g was classified as albuminuria., Results: Change in GFR was positively associated with a change in albumin-to-creatinine ratio in the entire cohort in the multiple linear regression. The albumin-to-creatinine ratio follow-up -to-albumin-to-creatinine ratio baseline ratio increased by 8.0% (95% confidence interval, 1.4 to 15.0) per SD increase in change in GFR. When participants with increased GFR (n=343) were compared with those with a reduced GFR (n=903), the ratio increased by 16.3% (95% confidence interval, 1.1 to 33.7). The multivariable adjusted odds ratio for incident albuminuria (n=14) was 4.98 (95% confidence interval, 1.49 to 16.13) for those with an increased GFR (yes/no)., Conclusions: Increasing GFR is associated with an increase in albumin-to-creatinine ratio and incident albuminuria in the general nondiabetic population. These findings support single-nephron hyperfiltration as a risk factor for albuminuria in the general population., (Copyright © 2016 by the American Society of Nephrology.)

MRI can provide excellent detail of renal structure and function. Recently, novel MR contrast mechanisms and imaging tools have been developed to evaluate microscopic kidney structures including the tubules and glomeruli. Quantitative MRI can assess local tubular function and is able to determine the concentrating mechanism of the kidney noninvasively in real time. Measuring single nephron function is now a near possibility. In parallel to advancing imaging techniques for kidney microstructure is a need to carefully understand the relationship between the local source of MRI contrast and the underlying physiological change. The development of these imaging markers can impact the accurate diagnosis and treatment of kidney disease. This study reviews the novel tools to examine kidney microstructure and local function and demonstrates the application of these methods in renal pathophysiology., (Copyright © 2016 the American Physiological Society.)

Objectives: The participation of vasopressin in the mechanisms of resistant hypertension is unclear. We compared plasma copeptin concentration, a surrogate marker for vasopressin secretion, between patients with resistant hypertension and those with controlled blood pressure (CBP), in a post hoc analysis of the Prise en charge de l'Hypertension Artérielle RESistante au traitement trial., Methods: After 4-week treatment with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day, and amlodipine 5 mg/day (baseline), 166 patients were classified as having resistant hypertension (n = 140) or CBP (n = 26) by ambulatory BP monitoring. Patients with resistant hypertension were then randomized for 12 weeks of sequential nephron blockade (n = 74) or sequential renin-angiotensin system blockade (n = 66). Plasma copeptin concentration was measured at baseline and week 12 by immunoassay., Results: Baseline plasma copeptin concentration was positively associated with male sex, plasma osmolality, BP, and negatively with glomerular filtration rate. It was higher in the resistant hypertension than in the CBP group [geometric mean 5.7 (confidence interval 95% 5.1-6.4) vs. 2.9 (2.3-3.9) fmol/ml, adjusted P < 0.0001). The relationship between plasma copeptin concentration and urinary osmolality was similar in the two groups. At 12 weeks, plasma copeptin concentration in patients whose BP was controlled by sequential nephron blockade or sequential renin-angiotensin system blockade [6.8 (5.6-8.2) and 4.3 (3.0-5.9) fmol/ml, respectively) remained significantly higher than in patients with CBP at baseline (P < 0.0001 vs. both)., Conclusion: In patients with resistant hypertension, plasma copeptin concentrations were approximately two-fold higher than those of patients with CBP, after adjustment for plasma osmolality. This difference was not accounted for by renal resistance to vasopressin, suggesting a primary reset of osmostat.