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Introduction Familial hyperkalemic hypertension is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, the variants of these genes cause disruption in the regulation of ion transport in the distal renal tubule. Whether the genotype explains the large phenotypic heterogeneity has not been fully explored. Methods We retrospectively analyzed clinical and genetic data of 153 cases (84 probands, 69 relatives) with familial hyperkalemic hypertension. Results Pathogenic variants (25 novel variants) were identified as follows: KLHL3 (n = 50), CUL3 (n = 16), WNK1 acidic motif (n = 11), WNK4 acidic motif (n = 4) and WNK1 intron 1 deletions (n = 3). De novo cases were mainly observed in the CUL3-related cases (9 of 12) and recessive cases were only observed in KLHL3-related cases (14 of 50). More severe forms were observed in recessive KLHL3 and CUL3 cases that were also associated with growth retardation. Patients with WNK1 acidic motif variants had a typical biological phenotype and lower frequency of hypertension conversely to WNK4 variants affecting the same motif. Patients with heterozygous KLHL3 and WNK1 deletions had milder forms. Familial screening in 178 relatives allowed detection and care for 69 positive cases. Blood pressure and hyperkalemia were improved by hydrochlorothiazide in all groups. Conclusions This study confirms the phenotypic variability ranging from the severe and early forms associated with CUL3 and recessive KLHL3 genotypes through intermediate forms associated with KLHL3 dominant, WNK4 and WNK1 deletion to mild form associated with WNK1 acidic motif genotype and reinforces the interest of genetic screening to better orientate medical care and genetic counseling., Graphical abstract

Hyperkalemia is a frequent complication among kidney transplant recipients that can lead to fatal arrhythmias. The causes of hyperkalemia post kidney transplant are multifactorial and often are drug-induced, and include decreased glomerular filtration rate, tubular dysfunction, and impaired sodium delivery in the distal nephron. This review will discuss pathophysiology and recent updates in the management of both acute and chronic hyperkalemia with a focus on kidney transplant recipients.

Hyperkalemia is a frequent complication among kidney transplant recipients that can lead to fatal arrhythmias. The causes of hyperkalemia post kidney transplant are multifactorial and often are drug-induced, and include decreased glomerular filtration rate, tubular dysfunction, and impaired sodium delivery in the distal nephron. This review will discuss pathophysiology and management of both acute and chronic hyperkalemia in kidney transplant recipients.

Objective: Vasopressin increases water permeability and activity of the epithelial sodium channel ENaC in the distal nephron of the kidney, favoring increased water and sodium retention. We hypothesized that genetically mediated differences in circulating vasopressin concentrations could contribute to features of hypertension that vary between non-Hispanic blacks and whites. To test this hypothesis we measured copeptin, a fragment of pre-pro arginine vasopressin with a prolonged half-life that is more easily quantified. Methods: The Genetic Epidemiology of Responses to Antihypertensives (GERA) I study was designed to identify predictors of response to diuretic therapy in non-Hispanic black and non-Hispanic white adults with essential hypertension. Blood samples were obtained after a 4 week washout of anti-hypertensive medication while on a sodium intake of 2 mmol/kg. Copeptin was measured from thawed EDTA plasma samples using the copeptin proAVP homogeneous automated immunofluorescent assay on the BRAHMS Kryptor Compact PLUS (Thermo Fisher). Results: Copeptin was significantly higher in blacks (median: 7.4 pmol/L, IQR: 4.4-10.2 pmol/L) than in whites (median: 5.4 pmol/L, IQR: 3.6-8.0 pmol/L) (p Conclusions: Higher copeptin (vasopressin) concentrations in non-Hispanic blacks compared to whites may contribute to the distinct differences in the hypertensive phenotypes between these racial groups. The underlying mechanism(s) require further study.

Kidney injury is a common finding in patients with liver disease. Bile cast nephropathy (also known as cholemic nephropathy) is an overlooked cause of renal injury in patients with hyperbilirubinemia. It can occur as a result of the toxic effects of bilirubin and bile acids on the renal tubules via several mechanisms. Bile cast nephropathy has characteristic histopathological changes consisting of bilirubin cast deposition in the distal nephron along with tubular epithelial cell injury. Treatment is based on the reversal of liver injury. This review aims to describe bile cast nephropathy in terms of its clinical and morphological features and to shed light on diagnostic techniques. In addition, we present data on management of such nephropathy while reviewing all the reported cases of bile cast nephropathy.

Chromophobe renal cell carcinoma (chRCC) represents 5% of all RCC. ChRCC appears to arise from the distal nephron, in contrast to clear cell RCC that arises from the proximal nephron. ChRCC is distinctive because the tumor cells contain abundant abnormal mitochondria, and frequently have loss of one copy of multiple chromosomes, with a low rate of somatic mutations. Here, we focus on recent discoveries related to genetic and metabolic factors that may promote the progression of chRCC and summarize how these findings may relate to the prognosis and treatment of chRCC.

Glycolytic activity is increased in proliferating cells, leading to the concept that glycolysis could be a therapeutic target in cystic diseases and kidney cancer. Preclinical studies using the glucose analog 2-deoxy-d-glucose have shown promise; however, inhibiting glycolysis in humans is unlikely to be without risks. While proximal tubules are predominantly aerobic, later segments are more glycolytic. Understanding exactly where and why glycolysis is important in the physiology of the distal nephron is thus crucial in predicting potential adverse effects of glycolysis inhibitors. Live imaging techniques could play an important role in the process of characterizing cellular metabolism in the functioning kidney. The goal of this review is to briefly summarize recent findings on targeting glycolysis in proliferative kidney diseases and to highlight the necessity for future research focusing on glycolysis in the healthy kidney.

Hyperkalemia results either from the shift of potassium out of cells or from abnormal renal potassium excretion. Cell shift leads to transient increases in the plasma potassium concentration, whereas decreased renal excretion of potassium leads to sustained hyperkalemia. Impairments in renal potassium excretion can be the result of reduced sodium delivery to the distal nephron, decreased mineralocorticoid level or activity, or abnormalities in the cortical collecting duct. In some instances, all 3 of these perturbations are present. Excessive intake of potassium can cause hyperkalemia but usually in the setting of impaired renal function. We discuss the clinical manifestations of hyperkalemia and outline an approach to its diagnosis and treatment.

In recent years, our understanding of the physiology of the aldosterone-sensitive distal nephron (ASDN) has greatly advanced thanks to the discovery of the complex with-no-lysine kinase (WNK) signaling and the molecular characterization of the epithelial sodium channel (ENaC). A series of studies, initially focused on rare tubulopathies such as Gordon and Liddle syndromes, eventually led to a partial elucidation of the so-called "aldosterone paradox", the traditional explanation of the physiology of such disparate conditions such as hyperkalemia and low effective arterial blood volume. The physiology of the ASDN is herein illustrated in light of the novel acquisitions in an easy-to-understand fashion, with the aim of giving the practicing nephrologist a solid "first glance" into this exciting but challenging field. Focus is on ion channels and transporters, their regulation by key hormones such as aldosterone and angiotensin II, and dietary implications.

Dopamine receptor subtype 4 (D4R) antagonists, such as clozapine, are used in the treatment of schizophrenia. A common side effect of clozapine is hypertension but the mechanism of the clozapine-in...

Aims Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium-conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure. Methods and results Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P

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.

The kidney continuously adapts daily renal excretion of NaCl to match dietary intakes in order to maintain the NaCl content of the body, and keep vascular volume constant. Any situation that leads to NaCl retention favors a rise in blood pressure. The aldosterone-sensitive distal nephron, which contains two main types of cells, principal (PC) and intercalated (IC) cells, is an important site for the final regulation of urinary Na(+) excretion. Research over the past 20 years established a paradigm in which PCs are the exclusive site of Na(+) absorption while ICs are solely dedicated to acid-base transport. Recent studies have revealed the unexpected importance of ICs for NaCl reabsorption. Here, we review the mechanisms of Na(+) and Cl(-) transport in the aldosterone-sensitive distal nephron, with emphasis on the role of ICs in maintaining NaCl balance and normal blood pressure.

PURPOSE OF REVIEW The study of inherited renal sodium (Na) transport disorders has greatly benefited from the use of new molecular biology research tools. This review discusses the recent findings that have expanded our knowledge and may impact clinical decision-making. RECENT FINDINGS The genetic and molecular biology diagnostic tools have to a large extent validated conclusions drawn from physiologic studies that documented suppressed or enhanced Na transport in specific distal nephron segments in various disorders. However, many surprises were also encountered. In several conditions, no mutation in the Na transporter itself was found despite apparent dysfunction of the transporter. Further search has led to discovery of additional mechanisms. Some involve mutations in other transporters, especially potassium (K) and chloride (Cl) channels, which secondarily affect function of the Na transporter by altering electrochemical gradients across the cell membrane. Examples include certain types of Bartter syndrome. In other patients, search for mechanism has led to discovery of novel physiologic regulatory pathways that, if abnormal, will lead to up- or downregulation of an Na transporter. Examples include some types of Bartter syndrome and Gordon syndrome. Genetic diagnosis has also revealed hitherto unexplained phenotypic heterogeneity between patients carrying the same mutation, implying a contributory role for other factors. SUMMARY Genetic and molecular diagnosis will have an expanding role in the understanding and management of the Na transport disorders. Predicting prognosis and inheritance pattern, as well as treatment plans will in the future be based on genetic diagnosis.

Renal acid-base balance may become deranged in a number of ways, some of which are the consequence of inherited disorders. Two main groups of distal renal acidopathies result either from a direct inability to secrete acid in the distal nephron (giving rise to type 1 renal tubular acidosis [RTA]) or

The renal mechanisms underlying sodium retention during liver cirrhosis have been difficult to elucidate. Kim and associates describe a biphasic pattern of regulation of the renal epithelial sodium channel in the common bile duct ligation model, shedding some light on this issue.

Renal tubular disorders in childhood are rare, but, when present, may produce profound electrolyte and volume disturbances. Children with hereditary tubular dysfunction commonly present in the first year of life with failure to thrive and other non-specific symptoms. Biochemical analysis of both serum and urine, together with clinical history and examination, remain fundamental for their diagnosis, whilst localization of the renal tubular defect to the proximal or distal nephron is necessary for understanding of the underlying pathophysiology and appropriate management. During recent years, important new information concerning diagnosis and treatment of selective tubular disorders has been acquired.

Primary cilia are hair-like organelles singly distributed along the apical surface of proximal and distal nephron tubules as mechanosensors. The goal of this study was to use electron microscopy to systemically evaluate cilia changes in acute tubular injury (ATI) from both transplant and native renal biopsies. Three groups of cases were included: control group 1-native biopsies without major changes in renal tubules; study group 2-native biopsies with prominent ATI; and study group 3-renal transplant biopsies with prominent ATI (delayed renal function group). Extensive search for ciliary structures along renal tubules was conducted in each case, focused on proximal tubular areas with injured (diminished) apical microvilli. Singly located cilia were found in 3/19 specimens in control group 1, 4/18 in group 2 (native ATI), and 6/24 in group 3 (transplant ATI). Importantly, there were clusters of cilia in proximal tubules with markedly diminished apical microvilli in 3/24 biopsies from 2 patients in group 3, but none from groups 1 and 2. The clusters of cilia ranged from 6 to 15 individual cilia along the apical surface with diminished apical microvilli. Under high magnifications, the cilia demonstrated 9 pairs of peripheral microtubules without a central pair of microtubules, consistent with primary cilia (9 + 0) rather than motile cilia (9 + 2). In summary, the authors found clusters of cilia in proximal tubules with remarkable apical microvillar injury in 3 renal transplant biopsies with ATI, implying a reactive, or repairing, process following tubular injury, thus they name this finding "cilia metaplasia".

Carcinoma of the collecting ducts of Bellini are rare aggressive neoplasms of distal nephron origin; it accounts for 2% of all renal cell carcinomas. Clinically, collecting duct carcinoma (CDC) is characterized by an extremely aggressive phenotype, accompanying metastatic diseases at presentation in most reported cases. Most cases of CDC have been reported with median age above 50 years. To our knowledge, this is the only second case report of CDC in a young teenager patient below 19 years with metastasis to lungs and bones at presentation.

Clinical findings resemble those of primary hyperaldosteronism, except that aldosterone secretion is negligible. The fault appears to lie with continuously avid sodium channels in the distal nephron, resulting in excessive salt absorption, potassium wasting, and severe hypertension. Insights gained in this disorder may help clarify more common forms of low-renin hypertension.

The thick ascending limb of the loop of Henle reabsorbs 20–30% of filtered sodium chloride (NaCl) and generates the osmotic gradient necessary for water absorption in the distal nephron. It is second

Background Epithelial cells are exposed to a variety of mechanical stimuli. Epithelial Na+ channels (ENaC) mediate sodium transport across apical membranes of epithelial cells that line the distal nephron, airway and alveoli, and distal colon. Early investigations into stretch sensitivity of ENaC were controversial. However, recent studies are supportive of ENaC's mechanosensitivity. This work studied whether flow-dependent activation of ENaC is modulated by changes in the state of the actin cytoskeleton and whether small GTPase RhoA is involved in flow-mediated increase of ENaC activity. Findings Pretreatment with Cytochalasin D and Latrunculin B for 20 min and 1-2 hrs to disassemble F-actin had no effect on flow-mediated increase of amiloride-sensitive current. Overexpression of ENaC with constitutively active (G14V) or dominant negative (T19N) RhoA similarly had no effect on flow-dependent activation of ENaC activity. In addition, we did not observe changes when we inhibited Rho-kinase with Y27632. Conclusions Our results suggest that the flow-dependent activation of ENaC is not influenced by small GTPase RhoA and modifications in the actin cytoskeleton.

Recently, the focus of interest on the role of the renin angiotensin system in the pathophysiology of hypertension has shifted towards greater emphasis on new developments in local renin angiotensin systems in specific tissues. We have focused our recent investigations on the role of the intrarenal-intratubular RAS in hypertension. All of the components needed for angiotensin II generation are present within the various compartments in the kidney. This brief review is focused on recent evidence that inappropriate activation of renin in distal nephron segments, by acting on angiotensinogen generated in the proximal tubule cells and delivered to the distal nephron may contribute to increased distal intrarenal angiotensin II formation, sodium retention and development and progression of hypertension.

Renal tubular disorders are uncommon in the newborn period, but, when present, they may produce complex life-threatening alterations in the composition of the intracellular and extracellular fluid compartments. Because of the infrequency with which these disorders are encountered; clinicians are often uncertain of the appropriate diagnostic evaluation. The authors believe that localizing major neonatal renal tubular disorders to the proximal and distal nephron will assist physicians in developing a pathophysiologic understanding of these conditions.

In acute interstitial nephritis (AIN), mononuclear cells invade the tubules (tubulitis). The segmental localization of tubulitis is not precisely known. To clarify this question, formalin-fixed kidney biopsy specimens from 13 patients with AIN were studied stereologically by identifying cortical tubules with segment-specific markers. The periodic acid-Schiff reaction, peanut lectin, and antibodies against Tamm-Horsfall protein and epidermal cytokeratins all applied to the same section were used to identify the proximal tubules (PTs), distal convoluted tubules, distal straight tubules, and the cortical collecting system (connecting tubules and cortical collecting ducts), respectively. Morphometrically, an estimate of the relative volume of the inflammatory cell infiltrates within each category of tubular segments was obtained. Inflammatory cells were infrequently found in PTs (1.2%) but were frequently localized in distal tubules and the cortical collecting system (7.6%). There was no difference in the amount of the inflammatory cell infiltrate within these segments. Re-examination of an electron microscopic study of AIN carried out in this laboratory revealed that mononuclear cells were rarely seen in convoluted PTs but were frequently observed in straight PTs and all segments distal to them. The observations indicate that it is the distal nephron which is primarily affected by inflammatory cell infiltration in AIN.

All of the components needed for angiotensin II generation are present within the renal tubular network of the kidney. This brief review is focused on recent evidence demonstrating that inappropriate activation of renin in distal nephron segments by acting on angiotensinogen generated in the proximal tubule cells and delivered to the distal nephron may contribute to increased distal intrarenal angiotensin II formation, sodium retention, and development and progression of hypertension. Moreover, mechanisms regulating collecting duct renin during Ang II-dependent hypertension are discussed.

To determine whether the lithium clearance (CLi) method offers a distinct advantage in the assessment of distal nephron function in the isolated perfused rat kidney (IPRK), estimates of distal Na+ reabsorption (dTNa+) based on the CLi (dTNA (Li)) were compared to those based on free water clearance (dTNa+(H2O)). In the steady state, dTNa+ (Li) was as high as 5-fold greater than (dTNa+(H2O)). The gap was even larger during the first hour of perfusion. These differences indicate that the Cu method is far superior and more accurate than the CH2O method, suggesting that it may be an adequate means for estimating dTNa+ in the IPRK. The CLi, observations also suggest that even in the absence of ADH a significant amount of solute-free water is reabsorbed by the collecting ducts of the IPRK.

La nefrosis del nefrón distal es uno de los problemas que han suscitado destacado interés en medicina. Iniciado, al parecer, por investigadores alemanes, al tratar de diferenciar las nefritis de las trincheras de una nefrosis especial consecutiva a la comprensión muscular, que fué observada durante la Primera Guerra Mundial y que Hackrad en 1917, denominó "Vaso motorischene fhose", indicando la importancia de la alteración vago motora en su patología así como la lesión tubular. Posteriormente fué estudiada con variadas denominaciones en razón de las diversidades etiológicas en que eran observadas; se le denominó nefritis parenquimatosa aguda, nefritis tubular aguda, síndrome de anoxia renal, nefrosis hemoglobinúrica, insuficiencia renal aguda, síndrome de anoxia renal en relación a causas tóxicas y traumáticas. Ultimamente, Kimmiltein la considera dentro de las nefrosis con el nombre de nefrosis tubular.

Growing infants must maintain a state of positive K+ balance, a task accomplished, in large part, by the kidney. The distal nephron is uniquely adapted to retain total body K+ early in life. The magnitude and direction of net K+ transport in the cortical collecting duct (CCD), the segment responsible for the final renal regulation of K+ balance in the adult, reflect the balance of opposing fluxes of K+ secretion and K+ absorption. Evidence now indicates that the low capacity of the neonatal CCD for K+ secretion is due, at least in part, to a relative paucity of conducting K+ channels in the urinary membrane. A relative excess of K+ absorption in this nephron segment may further reduce net urinary K+ secretion. Under conditions prevailing in vivo, the balance of fluxes in the CCD likely contributes to the relative K+ retention characteristic of the neonatal kidney.

We report 3 cases of a new renal cell tumor entity with a review of the literature. These 3 cases were retrieved from the files of this institution from 1991 to 2002. The clinical data and all histologic slides were reviewed and an immunohistochemical study was performed. Patients were all females. Tumors were almost similar with well-defined margins. Tumor architecture was tubular and focally fusiform with an abundant myxoid stroma. Tumor cells were low cuboidal, slightly eosinophilic with low nuclear grade. Immunohistochemistry was in favor of a distal nephron differentiation. All patients were healthy after surgery. We describe 3 cases of a new clinicopathological entity entitled low-grade tubular myxoid renal tumor with a benign clinical course.

Experimental acute kidney injury (AKI) is accompanied by the death of renal tubule epithelial cells, necrosis and apoptosis of the terminal portion of the proximal tubule, and apoptosis in the distal nephron. While immune competent cells invading the kidney play a role in such cell death, intervention in these processes only partially ameliorates the extent of cell death. Given the results of Linkermann et al. in this issue of KI, an epithelium-derived component of immune mediated cell death must now be strongly considered.

In recent years, the study of monogenic forms of hypertension has added greatly to our understanding of the regulatory mechanisms affecting blood pressure. Recently, a novel such form of human hypertension caused by gain-of-function mutation in the mineralocorticoid receptor, the mediator of aldosterone-induced sodium transport in the distal nephron, has been described, with the notable finding being that pregnancy causes a severe worsening of blood pressure. In this review, the mechanism by which the mutation causes hypertension, and the implications these findings have for improved understanding of cardiovascular physiology and mineralocorticoid receptor biology, are discussed.

The filtered calcium (Ca2+) is reabsorbed by the luminal membrane of the proximal and distal nephron. Ca2+ enters cells across apical plasma membranes along a steep electrochemical gradient, through Ca2+ channels. Regulation by various hormones implies several steps, including binding of these hormones to the basolateral membrane, interaction with G proteins, liberation of messengers, activation of kinases and finally opening of the channels at the opposite pole of the cells. In the present study, we examined whether the Ca2+ entry through the luminal membranes of proximal and distal tubules is also regulated by G proteins, by a membrane-limited process. Luminal membranes were purified from rabbit proximal and distal tubule suspensions, and their vesicles were loaded with GTPγs or the carrier. Then, the 45Ca2+ uptake by these membrane vesicles was measured in the presence and absence of 100 mM NaCl. In the absence of Na+, intravesicular GTPγs significantly enhanced 0.5 mM Ca2+ uptake by the proximal membrane vesicles from 0.53 ± 0.06 to 0.72 ± 0.06 pmol/µg/10 s (p < 0.05). In the presence of Na+, however, this effect disappeared. In the distal tubules, intravesicular GTPγs increased 0.5 mM Ca2+ uptake in the absence (from 0.57 ± 0.02 to 0.79 ± 0.02 pmol/µg/10 s, p < 0.02) and in the presence (from 0.36 ± 0.03 to 0.55 ± 0.03 pmol/µg/10 s, p < 0.02) of Na+. The action of GTPγs, when present, was dose dependent with a half-maximal effect at 20 µM. The distal luminal membrane is the site of two Ca2+ channels with different kinetics parameters. GTPγs increased the Vmax value of the low-affinity component exclusively, in the presence as in the absence of Na+. Finally, Ca2+ uptake by the membranes of the two segments was differently influenced by toxins: cholera toxin slightly stimulated transport by the proximal membrane, but had no influence on the distal membrane, whereas pertussis toxin decreased the cation uptake by the distal tubule membrane exclusively. We conclude that the nature of Ca2+ channels differs in the proximal and distal luminal membranes: Ca2+ channels present in the proximal tubule and the low-affinity Ca2+ channels present in the distal tubule membranes are directly regulated by Gs and Gi proteins respectively, whereas the high-affinity Ca2+ channel in the distal tubule membrane is insensitive to any of them.

Editor,—We read with interest the commentary by Claria and Rodes ( (1999) Gut 45:639–639; [OpenUrl][1][Abstract/FREE Full Text][2] ) on our paper published in Gut which re-examined the mechanisms of renal sodium retention in patients with preascitic cirrhosis.1 In summary, in our patients we observed indirect evidence of expanded central vascular fluid volume compared with healthy controls and thought this physiopathological alteration was due to slightly reduced values of glomerular filtration rate (measured as creatinine clearance) and, mainly, to increased distal tubular retention of sodium when expressed as a fraction of the filtered sodium load that is reabsorbed by the distal nephron (26.9 (6.7)% v 12.5 (3.4)%, respectively; p

1. Treva Caraway Ingram, MD 2. John M. Olsson, MD 1. Brody School of Medicine East Carolina University Greenville, NC Fluid and Electrolytes: Clinical Aspects. Hellerstein S. Pediatr Rev.1993;17 :103– 115[OpenUrl][1] Potassium Homeostasis and Hypokalemia. Linshaw MA. Pediatr Clin North Am.1987;34 :649– 681[OpenUrl][2][PubMed][3][Web of Science][4] Disorders of Potassium. Schaefer TJ, Wolford RW. Emerg Med Clin North Am.2005;23 :723– 747[OpenUrl][5][CrossRef][6][PubMed][7][Web of Science][8] Potassium, the most abundant cation in the intracellular space, is involved in a number of homeostatic processes, including regulation of cellular metabolism and maintenance of intracellular volume and cellular resting membrane potential. Proper functioning of all tissues, especially muscles and nerves, depends on normal concentrations of potassium. Potassium concentrations are regulated principally by the kidneys, which secrete or reabsorb potassium in response to various signals. Aldosterone is the primary hormone regulating potassium excretion, but other agents and processes also affect it. Glucocorticoids, antidiuretic hormone, high urinary flow rate, and increased sodium delivery to the distal nephron increase potassium excretion; insulin and catecholamines decrease its excretion. Insulin and catecholamines also increase the … [1]: {openurl}?query=rft.jtitle%253DPediatr%2BRev.%26rft.volume%253D17%26rft.spage%253D103%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: {openurl}?query=rft.jtitle%253DPediatric%2Bclinics%2Bof%2BNorth%2BAmerica%26rft.stitle%253DPediatr%2BClin%2BNorth%2BAm%26rft.aulast%253DLinshaw%26rft.auinit1%253DM.%2BA.%26rft.volume%253D34%26rft.issue%253D3%26rft.spage%253D649%26rft.epage%253D681%26rft.atitle%253DPotassium%2Bhomeostasis%2Band%2Bhypokalemia.%26rft_id%253Dinfo%253Apmid%252F3295721%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [3]: /lookup/external-ref?access_num=3295721&link_type=MED&atom=%2Fpedsinreview%2F29%2F9%2Fe50.atom [4]: /lookup/external-ref?access_num=A1987H641000009&link_type=ISI [5]: {openurl}?query=rft.jtitle%253DEmergency%2Bmedicine%2Bclinics%2Bof%2BNorth%2BAmerica%26rft.stitle%253DEmerg%2BMed%2BClin%2BNorth%2BAm%26rft.aulast%253DSchaefer%26rft.auinit1%253DT.%2BJ.%26rft.volume%253D23%26rft.issue%253D3%26rft.spage%253D723%26rft.epage%253Dix%26rft.atitle%253DDisorders%2Bof%2Bpotassium.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.emc.2005.03.016%26rft_id%253Dinfo%253Apmid%252F15982543%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/external-ref?access_num=10.1016/j.emc.2005.03.016&link_type=DOI [7]: /lookup/external-ref?access_num=15982543&link_type=MED&atom=%2Fpedsinreview%2F29%2F9%2Fe50.atom [8]: /lookup/external-ref?access_num=000230779600008&link_type=ISI

For more than 15 years, there has been an ongoing debate regarding the nephron segment(s) most severely injured in acute renal failure (ARF) induced by an ischemic or toxic insult. Although some investigators have argued that the proximal tubule (and particularly the S3 segment) is the major target of injury in ARF, others have held the view that damage to the distal nephron [particularly the medullary thick ascending limb (MTAL) segment] plays a more important role in this disease. In this discussion, the first of three on different aspects of ARF that have been hotly debated, we have invited several experts to discuss their opinions on this issue. The goals of this first discussion (and the subsequent two articles in this forum) are to establish areas of consensus in each area of controversy and also to identify unanswered questions that represent important areas for future research.

Because hypertension is a significant underlying cause of cardio- and cerebrovascular morbidity and mortality, much effort has been devoted to identifying genetic risk factors for its development. Thus far, all known genetic causes of human hypertension involve dysregulation of sodium resorption in the distal nephron.

After over four decades since its introduction for the occasional treatment of “psychotic excitement” lithium is still a mainstay in the treatment and prophylaxis of manic-depressive disorders [1]. It is estimated that in Western countries 0.1% of the population is on maintenance lithium therapy.

Nephrol Dial Transplant