Dorothy K. Grange, M.D.

• Division of Genetics and Genomic Medicine
• Department of Pediatrics
• Washington University School of Medicine
• St. Louis, Missouri

Adapted from Amatschek S gastritis diet ����������� generic maxolon 10mg with visa, Haller M chronic gastritis frequently leads to generic maxolon 10 mg on line, Oberbauer R: Renal phosphate handling in human-what can we learn from hereditary hypophosphataemias Male patients are usually more severely affected than female patients granulomatous gastritis symptoms best maxolon 10mg, with variable penetrance gastritis diet for diabetics buy maxolon 10 mg fast delivery. There is apparently no correlation between the serum levels of phosphate and the severity of the disease gastritis esophagitis diet maxolon 10mg with visa. The earliest sign of the disease in children can be increased serum alkaline phosphatase levels gastritis diet ����� buy maxolon online from canada. The clinical presentation is usually found not at birth but later, during childhood and even in adulthood. Consequently, intestinal calcium absorption is enhanced, resulting in hypercalciuria. Growth rate can be restored, and the clinical manifestations of rickets and osteomalacia. In addition, approximately half of the patients described with the disease have alopecia. In a subset of affected kindreds, premature stop codons in the vitamin D receptor gene lead to the absence of the ligand-binding domain. Affected individuals report recurrent painful, calcified subcutaneous masses of up to 1 kg, often resulting in secondary infection and incapacitating mutilation. Hyperuricosuria, combined with dehydration or exercise, results in acute uric acid nephropathy and causes an obstructive acute renal failure. Affected subjects typically have very high urate fractional excretion (50% or higher) and their parents have intermediate levels. It is described in this chapter because the enzyme is specifically expressed in the proximal tubule. Patients usually appear normal at birth, but muscle weakness, tetany, convulsions, and rickets start to develop at 2 months of age. The disease is usually suspected from the clinical history and the presence of glucosuria despite normal serum glucose levels. Homozygotes can show glucosuria of more than 60 g/day, evidence of renal sodium wasting, mild volume depletion, and raised basal plasma renin and serum aldosterone levels. Other sugars are not found (fructose, pentoses, galactose, lactose, sucrose, maltose, and heptulose). Subjects with renal glucosuria should be able to store and use carbohydrates normally. In addition, the kidney filters approximately 4000 mmol of bicarbonate daily and must reclaim most of the filtered load to maintain acid-base balance. Luminal H+ is trapped by urinary buffers, including ammonium secreted by the proximal tubule, and phosphate. Clinical and functional studies allow classification into four types, historically numbered in the order of discovery: proximal (type 2), classical distal (type 1), hyperkalemic distal (type 4), and combined proximal and distal (type 3). Rare forms of hereditary proximal and distal renal tubular acidosis have been identified213-215 and are discussed here Table 45. It results in an abnormally low threshold for renal bicarbonate reabsorption because the distal nephron is unable to compensate and reabsorb the large bicarbonate load presented to it. However, distal acidification mechanisms are intact, and acid urine can be produced. The metabolic acidosis is generally mild and associated with hypokalemia, and although metabolic bone disease is common, nephrocalcinosis and nephrolithiasis are rare. Because of a lowering of the tubular threshold for bicarbonate reabsorption, once the plasma bicarbonate is reduced, the threshold can be reached and a steady state maintained at a serum concentration of approximately 15 mM. More than 50 cases have been described, predominantly from the Middle East and Mediterranean regions. The disorder is discovered late in infancy or early in childhood because of developmental delay, short stature, fracture, weakness, cranial nerve compression, dental malocclusion, and/or mental subnormality. Typical radiographic features of osteopetrosis are present, and histopathologic study of the iliac crest reveals unresorbed calcified primary spongiosa. The radiographic findings are unusual, however, in that cerebral calcification appears by early childhood and the osteosclerosis and skeletal modeling defects may gradually resolve by adulthood. Treatment involves alkali supplementation for the acidosis and, potentially, bone marrow transplantation for osteopetrosis. Clinical features include inability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, hypercalciuria, nephrocalcinosis, and nephrolithiasis. The dominant form is usually a mild disorder that can be discovered incidentally after a kidney stone episode. Serum bicarbonate concentrations are usually between 14 and 25 mmol/L, and serum potassium levels between 2. Nephrocalcinosis, kidney stones, or both are frequent, and rickets can be present. In adults, administration of alkali 1 to 3 mmol kg/day usually corrects the metabolic abnormality. In this regard, it is of interest that a Bartter-like syndrome has been described in patients treated with aminoglycosides such as gentamicin and amikacin, characterized by transient hypokalemia, metabolic alkalosis, hypomagnesemia with urinary magnesium wasting, and hypercalciuria, which resolve weeks after drug termination. Both of these chloride channels must bind to the -subunit of Barttin to be transported to the cell surface. In the absence of mutations, the recycling of potassium maintains a lumen-positive gradient (+8 mV). Postnatal findings include polyuria, polydipsia, failure to thrive, growth retardation, dehydration, low blood pressure, muscle weakness, seizures, tetany, paresthesias, and joint pain from chondrocalcinosis. Activation of the renin angiotensin aldosterone system from volume depletion, plus increased sodium load to the cortical collecting duct, leads to increased sodium reabsorption by the epithelial sodium channel, which is counterbalanced by potassium and hydrogen excretion, resulting in hypokalemia and metabolic alkalosis. Enhanced passive Ca2+ transport in the proximal tubule rather than active Ca2+ transport in the distal convoluted tubule explains the hypocalciuria. Patients suffer from arthritis due to chondrocalcinosis in several joints,257 possibly secondary to hypomagnesemia. Urinary prostaglandin E2 levels are normal,258 a finding compatible with the poor response observed to prostanoid synthetase inhibition. A careful history, as well as measurement of urinary chloride and detection of diuretics, should help differentiate among these conditions. Indomethacin has been widely used, for which elevations of urinary prostaglandin E2 have provided a rationale. They are primarily characterized by low or low-normal plasma renin concentration and saltsensitive hypokalemic hypertension, suggesting enhanced mineralocorticoid activity. E, Minimal plasma Mg2+ concentration (dashed line indicates the lower normal limit, 0. Horizontal lines indicate the median; the open symbol in the Barttin group indicates the digenic ClC-Ka/ClC-Kb disorder. The phenotypes are determined by deficiencies as well as by overproduction of steroids unaffected by the enzymatic defect. Hypertension is observed in only two of the three major subtypes of congenital adrenal hyperplasia (11-hydroxylase and 17-hydroxylase deficiencies), because metabolic blockade distal to 21-hydroxylase allows the formation of 21-hydroxyl groups necessary for mineralocorticoid precursor biosynthesis. Other clinical manifestations depend on the consequences of the enzymatic defect on androgen biosynthesis with either an increase (11-hydroxylase) or a decrease (17-hydroxylase) in production. In both deficiencies, overproduction of cortisol precursors that are metabolized to mineralocorticoid agonists or that have intrinsic mineralocorticoid activity induce volume and salt-dependent forms of hypertension. Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Because the androgen pathway is unaffected, prenatal masculinization occurs in female patients and postnatal virilization in both sexes. In severe 17-hydroxylase deficiency, both the 17-hydroxylase and 17,20-lyase activities are reduced or absent. This deficiency results in high mineralocorticoid activity and hypertension, and produces a female phenotype in all subjects due to the absence of sex steroid production in both the adrenal and gonads. Partial 17-hydroxylase deficiency leads to sexual ambiguity in male patients without hypertension. Genetic male patients reared as female patients also require estrogen replacement. Genetic male patients reared as male patients require surgical correction of their external genitalia and androgen replacement therapy. Black arrows in the lower panel refer to the location of inactivating mutations (pseudohypoaldosteronism type I), while pink arrows refer to location of activating mutations (Liddle syndrome). Glucocorticoid-remediable aldosteronism is associated with increased production of 18-hydroxycortisol and aldosterone metabolites. By screening the mineralocorticoid receptor in 75 patients with early onset of severe hypertension, Geller and colleagues identified a 15-year-old boy with severe hypertension, suppressed plasma renin activity, low aldosterone, and no other underlying cause of hypertension, who had a heterozygous missense mutation (S810L) in the mineralocorticoid receptor gene. Two L810 carriers had undergone five pregnancies, all of which had been complicated by marked exacerbation of hypertension with suppressed aldosterone levels. The S810L mutation alters a conserved amino acid, resulting in a constitutively active and altered mineralocorticoid receptor. In addition, progesterone and other steroids lacking 21-hydroxyl groups, normally mineralocorticoid receptor antagonists, become potent agonists. Spironolactone is also a potent agonist of L810, so its use is contraindicated in L810 carriers. A milder phenotype, or type 2 variant, also results from abnormal activity of the enzyme. It is an autosomal dominant hypertensive disorder caused by a chimeric gene duplication arising from unequal crossover between genes encoding aldosterone synthase and 11-hydroxylase,279 two highly similar genes with the same transcriptional orientation lying 45,000 base pairs apart on chromosome 8. Humans have two isozymes with 11-hydroxylase activity that are required for synthesis of cortisol and aldosterone, respectively. In addition to 11-hydroxylase activity, the latter enzyme has 18-hydroxylase and 18-oxidase activities and can synthesize aldosterone from deoxycorticosterone. However, some subjects have early-onset severe hypertension, hypokalemia, and metabolic alkalosis. Other biologic features include hyponatremia, high plasma and urinary aldosterone levels despite hyperkalemia, and elevated plasma renin activity. Administration of aldosterone, fludrocortisone, or deoxycorticosterone is not helpful. Patients with the recessive form usually need lifelong treatment for salt wasting and hyperkalemia, whereas for those with the dominant form, treatment can usually be withdrawn in adulthood. Stowasser and colleagues reported five families with this phenotype with a segregation pattern supporting dominant inheritance. Hypertension is attributable to increased renal salt reabsorption, and hyperkalemia to reduced renal K+ excretion. Reduced renal H+ secretion is also commonly seen, resulting in metabolic acidosis. The action of these kinases may serve to increase salt reabsorption and intravascular volume in volumedepleted states and decrease potassium secretion in K depletion, by enabling the distal nephron to allow either maximal NaCl reabsorption or maximal K+ secretion in response to hypovolemia or hyperkalemia, respectively. The severity of hyperkalemia varies greatly and is influenced by prior intake of diuretics and salt. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are findings variably associated with the trait. Urinary concentrating ability, acid excretion, and proximal tubular function are all normal. Under normal conditions, extracellular magnesium concentration is maintained at nearly constant values (0. These inherited conditions affect different nephron segments and different cell types, leading to variable but increasingly distinguishable phenotypic presentations. Life-long magnesium supplementation is required to overcome the defect in the seizures and magnesium handling in these individuals. Hypomagnesemic patients have lower urinary excretion of calcium, presumably as a consequence of increased reabsorption in the loop of Henle. Renal calcium wasting is present in every case initially and leads to parenchymal calcification (nephrocalcinosis) and renal failure, often requiring dialysis. The progression rate of renal insufficiency correlates with the severity of nephrocalcinosis. Other clinical findings are polyuria, polydipsia, ocular abnormalities, recurrent urinary tract infections, and renal colic with stone passage. Serum levels of calcium, phosphorus, and potassium and urinary excretion of uric acid and oxalate are normal. These water channels are members of a superfamily of integral membrane proteins that facilitate water transport. These data have solved a longstanding physiologic puzzle-how membranes can be freely permeable to water but impermeable to protons. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. Two aspartate residues (in C1) coordinate two metal co-factors (Mg2+ or Mn2+, represented here as two small black circles), which enable the catalytic function of the enzyme. The dissociation of the A-kinase anchoring protein from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. These specialized permeability properties permit the excretion of large volumes of hypotonic urine formed during intervals of water diuresis. The clinical manifestations of polyuria and polydipsia can be present at birth and must be immediately recognized to avoid severe episodes of dehydration.

Kolonko A gastritis leaky gut purchase cheap maxolon online, Wiecek A: Contrast-associated nephropathy: old clinical problem and new therapeutic perspectives curing gastritis with diet order maxolon master card. Grobner T: Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis Maloo M gastritis diet lentils buy maxolon 10mg without a prescription, Abt P gastritis diet �� purchase maxolon discount, Kashyap R collagenous gastritis definition buy maxolon 10mg without prescription, et al: Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update gastritis prognosis order maxolon 10mg with mastercard. Food and Drug Administration: Gadolinium-based contrast agents: class labeling change-risk of nephrogenic systemic fibrosis. Cho R, Javed N, Traub D, et al: Oral hydration and alkalinization is noninferior to intravenous therapy for prevention of contrastinduced nephropathy in patients with chronic kidney disease. Trivedi H, Nadella R, Szabo A: Hydration with sodium bicarbonate for the prevention of contrast-induced nephropathy: a metaanalysis of randomized controlled trials. Tamura A, Goto Y, Miyamoto K, et al: Efficacy of single-bolus administration of sodium bicarbonate to prevent contrast-induced nephropathy in patients with mild renal insufficiency undergoing an elective coronary procedure. Zagler A, Azadpour M, Mercado C, et al: N-acetylcysteine and contrast-induced nephropathy: a meta-analysis of 13 randomized trials. Sun Z, Fu Q, Cao L, et al: Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials. El-Diasty T, Mansour O, Farouk A: Diuretic contrast-enhanced magnetic resonance urography versus intravenous urography for depiction of nondilated urinary tracts. Lezaic L, Hodolic M, Fettich J, et al: Reproducibility of 99mTcmercaptoacetyltriglycine renography: population comparison. Taghavi R, Ariana K, Arab D: Diuresis renography for differentiation of upper urinary tract dilatation from obstruction: F+20 and F-15 methods. Bosniak Morton A: the use of the Bosniak classification system for renal cysts and cystic tumors. Takase K, Takahashi S, Tazawa S, et al: Renal cell carcinoma associated with chronic renal failure: evaluation with sonographic angiography. Jinzaki M, Tanimoto A, Narimatsu Y, et al: Angiomyolipoma: imaging findings in lesions with minimal fat. Yamakado K, Tanaka N, Nakagawa T, et al: Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Nagase Y, Takata K, Moriyama N, et al: Immunohistochemical localization of glucose transporters in human renal cell carcinoma. Ozulker T, Ozulker F, Ozbek E, et al: A prospective diagnostic accuracy study of F-18 fluorodeoxy glucose-positron emmission tomography/computed tomography in the evaluation of indeterminate renal masses. Lyrdal D, Boijsen M, Suurkula M, et al: Evaluation of sorafenib treatment in metastatic renal cell carcinoma with 2-fluoro-2deoxyglucose positron emission tomography and computed tomography. Kotzerke J, Linne C, Meinhardt M, et al: [1-(11)C] Acetate uptake is not increased in renal cell carcinoma. Murakami M, Zhao S, Zhao Y, et al: Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Gutberlet M, Noeske R, Schwinge K, et al: Comprehensive cardiac magnetic resonance imaging at 3. Dunagin P, Alijani M, Atkins F, et al: Application of the kidney to aortic blood flow index to renal transplants. Before its routine use, only autopsy material was available to investigate the pathophysiology of kidney disease, limiting antemortem diagnosis. However, its development and refinement since the late 1950s has been fundamental for the diagnosis and definition of clinical syndromes and the discovery of new pathologic entities. The first percutaneous kidney biopsies were performed over 50 years ago using a liver biopsy needle and intravenous pyelograms for screening, with the patient either sitting or supine. Their success in obtaining renal tissue and in aiding management confirmed the benefit of the procedure. Indications for kidney biopsy may vary from center to center, but accepted indications are listed in Table 29. The significant complications related to the procedure are hemorrhage, development of arteriovenous fistulas, and to a lesser extent sepsis. There is a risk for formation of arteriovenous fistulas, which may be asymptomatic and spontaneously resolve or lead to a significant vascular steal syndrome, compromising the rest of the kidney through ischemia. Finally, there is the risk for sepsis following the procedure, through the introduction of a septic focus or its dissemination. Overall, the risks for complication vary from center to center and between practitioners but can be estimated to be between 3. Conversely, others using retrospective univariate analysis have reported blood pressure greater than 160/100 mm Hg or a serum creatinine level of more than 2 mg/dL more than doubled the risk for bleeding. In one small series, the results of ultrasonography performed within an hour after biopsy had a 95% negative predictive value for predicting clinically significant hemorrhagic complications,8 meaning that the absence of a hematoma on the postbiopsy scan was very suggestive of an uncomplicated clinical course. In part this is because its use was previously reserved for only those patients with prolonged bleeding times, and numerous studies have since demonstrated that complication rates are no different if bleeding time estimation is omitted from the preoperative assessment,11,12 because it does not predict clinical complications. The patients were normotensive and had preserved renal function with serum creatinine levels of less than 1. The patients given desmopressin demonstrated a significant reduction in postbiopsy bleeding from 30. However, the drop in hemoglobin level after biopsy was minimal, and there were no major complications, leading some to question the benefit of reduction in clinically unimportant hematomas, which can be frequently found following biopsy if looked for. Whether these data, in patients with preserved renal function, could be translated to those higher-risk patients with greater renal impairment is unclear and is a question worthy of a randomized trial. Guidelines on obtaining informed consent from patients and providing appropriate risk estimates have been produced by certain national renal groups, and one such example is provided in Table 29. These estimates may err on the conservative side and should be adapted to local practice if adequate complication data are available. There are certain absolute contraindications that preclude percutaneous biopsy, whereas there are a number of relative contraindications Table 29. Ideally, all efforts should be made to deal with the relative contraindications; however, in the context of acute kidney injury this may not always be possible. The critical preoperative steps are to ensure that blood pressure is controlled, that the patient does not have a bleeding diathesis or a urinary tract infection, and that the kidneys are suitably imaged, with no evidence of obstruction, widespread cystic disease, or malignancy (although percutaneous biopsy is increasingly used to diagnose the nature of renal masses). In these patients there are other means of obtaining renal tissue, which include open biopsies,14 laparoscopic biopsies, or transjugular biopsies. Overall, these are generally required for only a minority of potential biopsy patients. The safe duration of observation following kidney biopsy has been investigated in a number of studies. Findings suggest that early discharge (after only 4 hours of observation) will result in a number of missed complications, with many more occurring between 8 and 24 hours after the procedure. However, an overnight stay will allow an extra 20% of complications to be identified before discharge, with between 85% and 95% of complication being identified at 12 hours and 89% to 98% following 24-hour observation. Vigilant observation of blood pressure, pulse rate, and evidence of hematuria is required in all cases. The procedure is performed under sterile conditions with disposable sterile ultrasonographic probe covers, allowing real-time visualization of the kidneys. The procedure is generally performed with the patient under light sedation and with local anesthesia. The lower pole of the left kidney is commonly the biopsy site, but the kidney that is best visualized and most accessible is preferable. After skin preparation, a small incision is made to accommodate the biopsy needle, which is advanced until it reaches the renal capsule. The patient is asked to hold his or her breath while the needle biopsy mechanism is deployed. Needle size varies from 14 gauge to 18 gauge, with many using 16 gauge as a compromise between obtaining a suitable core and increasing the risk for bleeding. Two cores are taken, which should be divided for different assessments as outlined later. In these cases the biopsy is done through a coaxial introducer needle, and after biopsy the tract is plugged during removal of the coaxial introducer needle. Careful postprocedure observations of vital signs are performed to detect early signs of bleeding, and all urine is tested by dipstick for blood. Therefore it is necessary for the biopsy specimen to be divided to provide material for each of these methods of examination. During this process it is extremely important that the biopsy not be damaged by handling or by drying, and that the tissue be fixed using an appropriate fixative as quickly as possible, ideally within minutes. Examination of the biopsy specimen with a dissecting microscope allows cortex, containing glomeruli, to be distinguished from medulla and thus facilitates assessment of the adequacy of the cores and division of the biopsy specimen so that glomeruli are present in the samples for each modality of examination. If a dissecting microscope is not available, then a standard light microscope can be used with the biopsy specimen placed in a drop of normal saline on a microscope slide. The remainder of the cores can then be divided for light microscopy and for immunofluorescence. The part of the biopsy specimen for light microscopy is then placed in appropriate fixative and that for immunofluorescence is either snap frozen or transported to the laboratory in suitable transport medium such as that described by Michel and colleagues20; tissue placed in this medium can remain for several days at room temperature without loss of antigens. During division of the biopsy specimen it is important not to introduce artifacts due to crushing or stretching. Forceps should not be used to pick up the specimen; this can be done using either a needle or a small wooden stick such as a toothpick. If the biopsy specimen has to be taken to the histology laboratory for division, this should be done as quickly as possible with the biopsy specimen wrapped in salinemoistened gauze or in tissue culture medium. Artifacts may be produced if the biopsy specimen is placed on dry gauze or gauze moistened with water, or if it is placed in ice-cold saline. If the amount of material obtained at biopsy is limited, then it may be necessary to adapt the way in which it is divided, and the decision as to how this is done must depend on the clinical question. In most cases it is possible to omit frozen material for immunofluorescence and instead perform immunohistochemical examination on paraffin sections. This is actually a 10% solution of the 37% commercially available concentrated solution of formaldehyde, giving a final concentration of approximately 4%. Details of the preparation of various fixatives can be found in the appendix of Churg and associates. Rapid processing schedules allow for same-day processing, and it is possible to obtain stained slides within 3 to 4 hours of receipt of the specimen in the laboratory. Because many pathologic lesions may be focal within glomeruli, interstitium, or vessels, it is essential that the biopsy be examined at multiple levels, and each laboratory will have its preferred way to achieve that. Multiple slides can then be stained with each stain, with some intervening unstained sections kept either for potential immunohistochemical examination or for other special stains as necessary. The H&E stain is a good general histologic stain for studying the overall architecture of the kidney. It is good for studying the morphology of tubular cells and the morphology of interstitial infiltrates. With experience the different staining characteristics of hyaline, fibrin, and amyloid, all of which are eosinophilic, can usually be distinguished. However, the H&E stain does not distinguish staining of glomerular matrix and basement membrane from cell cytoplasm and therefore is less useful for the assessment of glomerular architecture. Its only drawback is that a satisfactory result is more technically demanding than the other stains. The authors always use an elastin stain to demonstrate the elastic laminae of vessels, and this is counterstained with picrosirius red to stain fibrillar collagen in the interstitium. Amyloid is most specifically detected in a Congo red stain, and the authors feel it is prudent to perform this in all native kidney biopsy specimens. A lesion that involves all or nearly all glomeruli is described as diffuse, whereas one that involves some but not all glomeruli is described as focal. In the definitions given in the World Health Organization atlas of glomerular diseases, it was suggested that the cutoff for focal versus diffuse should be 80% of glomerular involvement. However, in later classifications of lupus glomerulonephritis and immunoglobulin A (IgA) nephropathy,22,23 the cutoff is defined as 50%. In the classifications of lupus glomerulonephritis and IgA nephropathy,22,23 the cutoff is set at 50% glomerular tuft involvement, except for segmental sclerosis in IgA nephropathy, in which any area of sclerosis that leaves some of the glomerulus unaffected is defined as segmental. There are a number of other terms, such as sclerosis and hyalinosis, that have specific definitions in the glomerulus, and these are listed in Table 29. Sections should first be assessed at low power to determine what parts of the kidney (or other structures in some cases) they contain, including whether there is cortex and/or medulla. A low-power view will also allow an assessment of the amount of chronic nephron damage, as demonstrated by tubular atrophy and interstitial fibrosis, and the presence of interstitial inflammatory infiltrates. It will also allow an assessment of interstitial expansion, most commonly due to either edema or fibrosis, but occasionally due to infiltration by, for example, amyloid. Examination should then proceed by studying the glomeruli, tubules, interstitium, and vessels, including arteries, arterioles, and veins, in more detail. Features that should be looked for in glomeruli and tubules are detailed in Tables 29. Arterioles should be examined for the presence of hyalinosis, thrombosis, and necrosis. Arteries should be assessed for intimal thickening and whether it is accompanied by reduplication of the internal elastic lamina, thrombosis, necrosis, inflammation, and cholesterol emboli. In transplanted kidney biopsy specimens staining for C4d is invaluable in assessing the activation of the classical pathway of complement by antibody and hence in the diagnosis of antibody-mediated rejection. There are a number of other antigens whose detection may be useful in particular circumstances. Lymphocyte surface antigens, particularly in cases of suspected lymphoid neoplasia. Fibronectin in fibronectin glomerulopathy Immunohistochemical testing is performed either on cryostat sections of a piece of snap frozen tissue or on paraffin sections.

However gastritis symptoms tongue order maxolon amex, elastography is also sensitive to mechanical and functional parameters such as hydronephrosis and external pressure gastritis diet 5 small discount maxolon 10mg online. Every experienced nephrologist has seen cases of obstruction with negative ultrasonographic study results gastritis symptoms in the morning order maxolon master card. Therefore the diagnosis of obstruction must still be considered in patients with worsening renal function gastritis diet ����� buy maxolon 10mg with visa, chronic azotemia gastritis diet ������24 buy 10 mg maxolon, or acute changes in renal function or urine output gastritis vomiting blood discount maxolon 10 mg, even in the absence of hydronephrosis on ultrasonography. However, in some cases of acute urinary obstruction, ultrasonography may fail to detect pathologic processes. Renal ultrasound elastography provides measurement of kidney elasticity by the Shearwave technique. This finding is important in the prenatal counseling and treatment of boys with bilateral hydronephrosis and marked bladder dilation. Persistent postnatal renal abnormalities appear likely when the anteroposterior diameter of the fetal renal pelvis measures more than 6 mm at less than 20 weeks, more than 8 mm at 20 to 30 weeks, and more than 10 mm at more than 30 weeks of gestation. The long-term morbidity of mild hydronephrosis (pelviectasis without calyceal dilation) is low. Cases of severe hydronephrosis (pelvicalyceal dilation with parenchymal thinning) may require surgical intervention for declining renal function, infection, or symptoms. Overall, because only approximately 5% to 25% of patients with antenatal hydronephrosis will ultimately require surgical intervention,102,137 careful long-term follow-up of these patients is required throughout childhood and into adulthood. However, in the absence of bilateral hydronephrosis, a solitary kidney, or suspected posterior urethral valve, functional imaging can be deferred until the first 4 to 6 weeks of life. In the United States most infants with prenatally detected hydronephrosis that is confirmed with postnatal studies are placed on antibiotic prophylaxis pending the outcome of further evaluation. However, an infection in the setting of ureteral obstruction can cause significant morbidity, resulting in an infant with sepsis, and renal damage is a potential comorbid condition. In urinary tract obstruction, pathophysiologic changes affecting the pressure in the collecting system and kidney perfusion are well imaged and form the basis for the correct interpretation of real-time ultrasonography and color duplex Doppler ultrasonography. As detailed earlier, ultrasonography is very sensitive for the detection of collecting system dilation ("hydronephrosis"); however, obstruction is not synonymous with dilation, because either obstructive or nonobstructive dilation may be present. A, Left hydronephrosis: dilated renal pelvis (arrows), with normal kidney on right. Isotopic renography is typically used to estimate the fractional contribution of each kidney to overall renal function. The noninvasive character of this examination with its high reproducibility makes it excellent for monitoring patients, and it helps the urologist to decide whether to perform surgical intervention or watchful waiting. Diuretic renography was introduced into clinical practice in 1978152 and may be used to distinguish between hydronephrosis or pelvic dilation with obstruction and dilation without obstruction. Following administration of radioisotope, when the isotope appears in the renal pelvis, a loop diuretic such as furosemide is given intravenously. If stasis is causing the dilation, the induced diuresis may result in prompt washout of the tracer from the renal pelvis. Magnetic resonance urographic image shows large dilation of the left pelvicalyceal system and narrowing of the left ureteropelvic junction segment. Misinterpretation can easily take place if the renal pelvis is very large and does not allow proper drainage within the study time, and drainage may be better estimated using new tools. Renal excretion of the tracer with a t 12 between 15 and 20 minutes is considered equivocal. An absent or blunted diuretic response resulting from decreased renal function or grossly dilated pelvis makes interpretation of the test difficult and limits its usefulness and may require support tools to increase the diagnostic performance. The classical variables of the diuretic renogram may not allow an estimate of the best drainage. Poor pelvic emptying may be apparent because the bladder is full and because the effect of gravity on drainage is incomplete. Estimating the drainage as residual activity rather than any parameter on the slope might be more adequate, especially if the time of furosemide administration is changed. A mixture of saline and contrast material is infused through the renal cannula at a rate of 10 mL/min, and pressures are monitored. The urinary tract is considered nonobstructed if renal pelvic pressure is less than 15 cm H2O, equivocal at a pressure between 15 and 22 cm H2O, and obstructed if pressure exceeds 22 cm H2O. When retrograde pyelography rarely is performed, this takes place during cystoscopy, by cannulating the ureteral orifice and injecting contrast. Retrograde pyelography can be combined with placement of a ureteral stent to relieve an obstruction, or with possible stone extraction. Because the procedure passes through the bladder to reach the upper urinary tract, the risk for introducing infection proximal to the obstruction must be kept in mind, and the obstruction should be relieved immediately after retrograde pyelography. Antegrade pyelography is performed by percutaneous cannulation of the renal pelvis and injection of the contrast material into the kidney and ureter. B, Stones (arrowheads) as filling defects in the distal ureter (not seen on plain film). Intravenous pyelography was unsuccessful owing to the obstructed and malfunctioning kidney. In these animal models the extent of obstruction is clear and reproducible, and, if the kidneys are studied soon after the obstruction is performed or released, the results are not confounded by changes in renal structure brought on by inflammation or fibrosis. Complete obstruction of short duration strikingly alters renal blood flow, glomerular filtration, and tubular function, while producing minimal anatomic changes in blood vessels, glomeruli, and tubules. Kf is determined by the permeability properties of the filtering surface and the surface area available for filtration. In fact, glomeruli of individual nephrons exhibit the same response in in vivo micropuncture experiments when antegrade urine flow is blocked by placement of a wax block in the tubule of the nephron. This hyperemic response is not attenuated by renal nerve stimulation or infusion of catecholamines,174 and it may be linked to changes in interstitial pressure. Similarly, because obstruction reduces urine flow past the macula densa, this structure induces afferent vasodilation. Indomethacin blocks the hyperemic response, which indicates that vasodilator prostaglandins are critical to afferent vasodilation. Increased efferent nerve activity to the right kidney was accompanied by reduced blood flow to that kidney. This vasoconstrictor response was ablated by denervation of either the left or right kidney before induction of left ureteral obstruction, which suggests that increased afferent renal nerve traffic triggers vasoconstrictive renorenal reflex activity that counteracts the early intrinsic renal vasodilator effects of obstruction in bilateral ureteral obstruction. In bilateral obstruction, renal blood flow is reduced to levels 30% to 60% below normal179,180,182 Table 38. First, release of obstruction strikingly augments the flow of tubule fluid past the macula densa. Although the absolute rate of flow is still far below normal, the macula densa likely senses the dramatic change in the rate of flow, and this may lead to intense vasoconstriction. Ureteral obstruction rapidly increases renal vein renin levels at a time when renal blood flow is normal or elevated, but at later time points, renal vein renin levels return to normal. In micropuncture studies, some nephrons never regain filtration function, whereas others reveal striking hyperfiltration. However, 15% of the glomeruli were not filtering in recovered kidneys, and other nephrons were hyperfiltering. In this model of complete obstruction, there appeared to be no selective advantage for surface glomeruli over deep cortical and juxtamedullary glomeruli. This demonstrates that early release of neonatal obstruction provides dramatically better protection of renal function than release of obstruction after the maturation process is completed. In obstruction, increased proportions of filtered salt and water are delivered to the loop of Henle in juxtamedullary nephrons J1 and J2, which indicates decreased reabsorption. In bilateral obstruction, there was net addition or secretion of salt and water into the lumen of the inner medullary collecting duct, which suggests that in this setting the inner medullary collecting duct secretes salt and water. Pathologically, prolonged obstruction leads to profound tubular atrophy and chronic interstitial inflammation and fibrosis (see later), whereas at early time points following the onset of obstruction, such as at 24 hours, there are only slight structural and ultrastructural changes, including mitochondrial swelling, modest blunting of basolateral interdigitations in the thick ascending limb and proximal tubule epithelial cells, as well as flattening of the epithelium and some widening of the intercellular spaces in the collecting ducts. As discussed later, regulation of tubular transport is complex and is due to both direct damage of epithelial cells and the action of extratubular mediators, arising from both the kidney and extrarenal sources. After release of bilateral obstruction, salt and water excretion jumps up to five to nine times normal. In these preparations, transport-dependent oxygen consumption was markedly reduced in cells isolated from animals with bilateral obstruction. Data from Buerkert J, Martin D, Head M, et al: Deep nephron function after release of acute unilateral ureteral obstruction in the young rat. Because these functional derangements occur in the absence of clear-cut ultrastructural damage to the epithelial cells, obstruction likely induces a selective impairment in the regulation of active cellular transport mechanisms. Unlike the situation with glomerular filtration, the functional impairment appears similar in both unilateral and bilateral obstruction. Added onto this intrinsic injury, natriuretic substances may be responsible for the apparent secretion of salt and water in the inner medullary collecting duct of animals following release of bilateral obstruction (see Table 38. A combination of studies of cell suspensions and antibodybased targeted proteomics in which long-term regulation renal transporters and channels can be examined in intact animals to understand the integrated response to obstruction has improved the molecular understanding of mechanisms by which tubular epithelial cell salt reabsorption is impaired in the setting of obstruction. Isotopic bumetanide binding revealed a marked reduction in the number of cotransporter protein molecules available for binding on the membrane, with no change in affinity of binding, which indicates that obstruction downregulates the expression of the cotransporter protein on the membrane surface. Interestingly, metabolic studies reveal that obstruction reduces activities as well of several enzymes of the oxidative and glycolytic pathways, consistent with a downregulation of metabolic capacity for energy generation in these cells. On this basis, it appears more likely that obstruction-induced reduction of epithelial sodium transport is a regulated process as a result of reduced metabolic demands during obstruction. The mechanisms and pathways responsible for downregulation of transport proteins in tubular epithelial cells by obstruction remain to a large extent incomplete. Possible signals include the halting of urine flow, increased hydrostatic pressure on tubular epithelial cells, changes in blood flow to the tubules or in interstitial pressure, and generation of natriuretic substances in the kidney that result in longterm inhibition of transporter function. These findings suggest that obstruction induces acute molecular changes in the renal cytoskeleton, in part mediated by increased stretch of the renal tubular cells during obstruction. Consequently, sodium delivery to each tubular segment is reduced, and apical membrane Na+ entry slows dramatically because the electrochemical gradients for Na+ entry between the stationary apical fluid and the cell interior become increasingly unfavorable for continued sodium transport. Reduced Na+ entry might then directly stimulate downregulation of transporter activity and expression. When apical Na+ entry was blocked either by substituting another cation for sodium in the apical solution, or by adding amiloride to the apical solution, apical sodium entry was markedly reduced for some hours after the blockade was removed. There is a strong labeling at the base of the inner medulla in obstructed kidneys located exclusively in the interstitial cells (B). In addition to the direct effects of halting urine flow, changes in intrarenal mediators and subcellular pathways likely play a critical role in the reduction of salt transport observed with obstruction. As discussed earlier, obstruction brings on a monocellular infiltrate in the kidney194; and this infiltrate tends to follow a peritubular distribution. When both ureters are obstructed, extrarenal factors markedly enhance the sodium-wasting tendency already present in the obstructed kidney. One mechanism involves the volume expansion that occurs when bilateral obstruction ablates all renal function. Following release of 24 hours of unilateral obstruction, removal or obstruction of the contralateral kidney markedly enhances salt wasting by the obstructed kidney. Indeed, interstitial osmolality has been shown to be reduced in obstructed kidneys. As was the case with sodium transport, the effects were similar in unilateral and bilateral obstruction. The collecting duct in obstructed kidneys maintains its low water permeability in the absence of antidiuretic hormone, so that the failure to dilute the urine is not due to collapse of osmotic gradients in the collecting duct. In humans, release of obstruction does not lead to bicarbonate wasting, which indicates that proximal tubule bicarbonate reclamation is maintained. By contrast, in both experimental animals and patients following release of obstruction, the urine pH does not decrease in response to an acid load, which indicates that obstruction impairs the ability of the distal nephron to acidify the urine. However, this disorder alone cannot account for the entire acidification defect in obstructive nephropathy, because the labeling pattern returns to control levels as the obstruction persists, whereas the acidification defect remains. In addition to defective collecting duct H+ transport, reduced generation of the main buffer that carries acid equivalents in the urine, ammonia, has also been observed in kidneys released from obstruction. Cortical slices of obstructed kidneys exhibit reduced glutamine uptake and oxidation, reduced gluconeogenesis, and reduced total oxygen consumption, all adding up to a reduced ability to generate ammonia from glutamine. However, administration of sodium sulfate in this state does not stimulate potassium excretion in obstructed kidneys as it does in controls, which suggests that collecting ducts in unilateral obstructed kidneys have an intrinsic defect in potassium secretion. This magnesium wasting probably occurs because both forms of obstruction markedly attenuate thick ascending limb sodium reabsorption, leading to reduced positive luminal transepithelial voltages and therefore a reduced driving force for lumen-to-basolateral magnesium flux across the paracellular pathway. It is thought that chronic obstruction damages tubular epithelial cells by increasing hydrostatic pressure, reducing blood flow (due to the renal vasoconstriction that occurs in obstruction, see earlier), and increasing oxidative stress. All these factors accelerate the development of interstitial fibrosis by increased extracellular matrix, cell infiltration, apoptosis, and accumulation of activated myofibroblasts. It has been hypothesized that changes in the intratubular dynamic forces-so-called tubular stretch-in urinary tract obstruction also are an important determinant for development of tubulointerstitial fibrosis in the kidney. Along this line, data suggest that mast cells also have the capacity to release chymase, a protease, which may limit development of tubulointerstitial fibrosis by decreasing infiltration of inflammatory cells and release of proinflammatory and profibrotic chemokines and cytokines. From multiple studies, it has been suggested that the main mechanism that is responsible for the onset of the pathophysiologic cascades is the increased pressure in the renal pelvis, which leads to increased pressure in the parenchyma and subsequently mechanical stress, which leads to activation of stretch and swelling-activated cation channels within focal adhesions of the epithelial cells, causing subsequent influx of Ca2+. Further, this finding may show implications for the design of novel potent therapies to overcome the shortcomings of global angiotensin receptor blockade. Thus the process leading to kidney fibrosis is complex, and numerous processes contribute to regulating the cellular changes that are responsible for these pathophysiologic changes. Given species differences and the fact that obstruction in humans is often partial, the animal models may not predict entirely the behavior of postobstructive kidneys in humans. However, if the studies are relevant to human obstructive nephropathy, they suggest that patients undergoing release of obstruction may benefit from therapies that block proapoptotic, proinflammatory, or profibrotic mediators or from treatments that stimulate epithelial cell growth and differentiation. These results support the view that inflammation is a crucial determinant for the onset of renal deterioration in urinary tract obstruction. However, in experimental models, obstruction in utero can cause pulmonary hyperplasia and renal impairment directly or indirectly, leading to significant morbidity and mortality. The type of intervention depends on the location of the obstruction, its degree, and its cause, as well as the presence or absence of concomitant diseases and complications, and the general condition of the patient.

Active caspase-8 activates caspase-3 and cleaves proapoptotic protein Bid to its truncated form tBid erythematous gastritis definition discount maxolon, which acts via Bax to induce cytochrome c from the mitochondria gastritis diet nhs purchase maxolon canada. Hence the extrinsic pathway also amplifies the events induced by the intrinsic pathway gastritis y diarrea cheap maxolon 10 mg line. It is not dependent on caspase activation but rather results from a rise in intracellular calcium and the activation of membrane phospholipases chronic gastritis group1 10 mg maxolon with mastercard. Increased cytosolic calcium causes further mitochondrial injury and cytoskeletal alterations gastritis symptoms light headed safe maxolon 10mg. Phospholipases such as phospholipase A2 cause direct hydrolytic damage to membranes and also release toxic free fatty acids chronic gastritis reversible order 10 mg maxolon with mastercard. They also cause release of eicosanoids that have vasoactive and hemokinetic activities, resulting in an intense surrounding inflammatory response. Calpain mediates plasma membrane permeability, as well as hydrolysis of the cytoskeleton proteins. The time course of involvement varies by the cell type142,183 with polymorphonuclear cells leading the way followed by monocytes/macrophages in both rapidity of response and numbers of cells. Red represents 3-kDa Texas Red dextran, which is filtered and labels the tubular lumens. Note apoptotic nuclei, which show intense Hoechst staining along with condensation and fragmentation (arrows). Many of these apoptotic nuclei are shed into the lumens of tubules with compromised urine flow. Also noted is the rouleaux formation and congestion in peritubular capillary with lack of blood flow (*). Blockade of neutrophil function or neutrophil depletion has been shown to provide only partial protection against injury. Complement cascades are activated during sepsis, and C5a, a potent complement component with procoagulant properties, has been found to be elevated in rodent models of sepsis. Blocking C5a or its receptor has shown some promise in improving survival with sepsis. Macrophages produce proinflammatory cytokines that can stimulate the activity of other leukocytes. Thus dendritic cells serve at the crossroads of communication between the epithelium and endothelium regulating both innate and adaptive immunity, self-tolerance, and tissue injury and repair. Liu and colleagues have shown that in a murine model of ischemic acute kidney injury there was a significant trafficking of Treg cells into the kidneys after 3 and 10 days. These studies demonstrate that Treg cells infiltrate ischemic-reperfused kidneys during the healing process promoting repair, likely through modulation of proinflammatory cytokine production of other T cell subsets. While the myofibroblast is the cell type responsible for depositing collagen, investigators have been searching for its precursors. Other than interstitial fibroblasts that are known to transition, pericytes and dendritic, endothelial, and epithelial cells have been identified as potential contributors. Thus dissociation of pericytes from their endothelial partners seems to be an early step initiated by alterations in communication between these two cell types or interstitial signals generated by many potential cell types. These events also suggest several therapeutic targets that could limit microvascular dropout and loss of kidney function secondary to the fibrotic process. However, there are protective mechanisms that allow cells to have a defense against numerous stresses. The complex hsp system is induced to exceptionally high levels during stress conditions. The hsps are believed to facilitate the restoration of normal function by assisting in the refolding of denatured proteins, along with aiding the appropriate folding of newly synthesized proteins. They also help in degradation of irreparable proteins and toxins to limit their accumulation. Thus their role has been studied, and it was found that overexpression before injury has protective effects. Repair, Regeneration, and Role of Stem Cells the renal tubular epithelial cells have the remarkable potential to regenerate functionally and structurally after ischemic or toxic insults. More severely injured cells can, however, undergo this stage, which morphologically appears as flattened cells with an ill-defined brush border. Essentially there is proliferation of the viable cells that spread across the denuded basement membrane, after which they regain their differential character back into a normal tubular epithelial cell. Lastly, although lipid polarity is eventually reestablished, it can lag behind reestablishment of protein polarity and is completed by approximately 10 days after injury. In animal models, administration of exogenous growth factors has been shown to accelerate renal recovery from injury. There has been a major interest in studying the roles of progenitor/stem cells and mesenchymal stem cells in tubular epithelial cell injury. Investigators have now shown that different types of stem cells may reside in the renal architecture. Bone marrow cells are known to migrate to the kidney and participate in normal tubular epithelial cell turnover and repair after acute kidney injury. Although the protective mechanisms have not yet been completely elucidated, they have been postulated to be less by direct differentiation into renal epithelial cells and more by paracrine effects such as supplying growth factors that stimulate the regeneration of tubular and resident stem cells. The "renotropism" exhibited by these cells may inform therapeutic options in the future once their roles are more fully defined. The renal vasculature and endothelium are particularly sensitive to these insults. When such an insult occurs, the endothelial bed becomes ineffective in performing its function, and the ensuing vascular dysregulation leads to continued ischemic conditions and further injury following the initial insult, which has been termed the extension phase of acute kidney injury. Vascular Tone the cytoskeletal structure of endothelial cells includes actin filament bundles that form a supportive ring around the periphery, along with the adhesion complexes that provide the integrity of the endothelial layer. With ischemic injury the normal architecture of the actin cytoskeleton is markedly changed along with endothelial cell swelling, impaired cell-cell and cell-substrate adhesion, and loss of tight junction barrier functions. This activity results in depolymerized and severed actin filaments, seen as F-actin aggregates at the basolateral aspects of the cell. It is defined by a combination of transcellular and paracellular pathways, the latter being a major contributor to the inflammation-induced barrier dysfunction. Sutton and associates have studied the role of endothelial cells in acute kidney injury by a series of experiments utilizing florescent dextrans and two-photon intravital imaging. These investigators have shown that 24 hours after ischemic injury there was loss of localization in vascular endothelial cadherin immunostaining, suggesting severe alterations in the integrity of the adherens junctions of the renal microvasculature. The protein C pathway helps to maintain normal homeostasis and limits inflammatory responses. Protein C is activated by thrombin-mediated cleavage, and the rate of this reaction is further augmented 1000-fold when thrombin binds to the endothelial cell surface receptor protein thrombomodulin. Activated protein C essentially then has antithrombotic actions and profibrinolytic properties and participates in numerous antiinflammatory and cytoprotective pathways to restore normal homeostasis. Activated leukocytes adhere to endothelial cells through these adhesion molecules. The combination of leukocyte adhesion and activation, platelet aggregation, and endothelial injury serves as the platform for vascular congestion of the medullary microvasculature. There are permeability defects between endothelial cells as a result of tight and adherens junctional alterations. It has been shown that both pretreatment and postinjury treatment with soluble thrombomodulin attenuates renal injury with minimization of vascular permeability defects with improvement in capillary renal blood flow. Leukocyte activation and its release of cytokines require signals through chemokines circulating in the bloodstream or through direct contact with the endothelium. Rolling leukocytes can be activated by chemoattractants such as complement C5a and plateletactivating factor. Once activated, leukocyte integrins bind to endothelial ligands to promote firm adhesion. These interactions with the endothelium are mediated through endothelial adhesion molecules that are upregulated during ischemic conditions. Singbartl and colleagues have found that platelet P-selectin and not endothelial P-selectin was the main determinant in neutrophil-mediated ischemic renal injury. Furthermore, selectindeficient mice demonstrated similar intraperitoneal leukocyte recruitment but altered cytokine levels when compared to wild-type mice. Hence T cells directly contribute to the increased vascular permeability, potentially through T cell cytokine production. It is not clear yet whether apoptosis and/or necrosis play a major role in endothelial cell dropout. The profibrotic response was significantly attenuated in rats treated with apocynin. Targets of Therapy-Role of Endothelial Progenitor Cells generated by neighboring cells or cells recruited from the circulation. Effects of Acute Kidney Injury on Distant Organs Due to the numerous mechanisms in initiating and continuing existing injury, there are several targets available to reduce the effect of endothelial cell injury and potentially minimize actual endothelial cell damage itself. The concept of restoration of vascular supply to damaged or ischemic organs for accelerating their regeneration is well established. One therapeutic strategy based on this concept is the delivery of angiogenic factors. Kelly and associates have demonstrated the effects of renal ischemia on cardiac tissues. There was also a significant increase in myeloperoxidase activity in the heart and liver, apart from the kidneys. At 48 hours, cardiac function evaluation by echocardiography also revealed increases in left ventricular end systolic and diastolic diameter and decreased fractional shortening. As little as 15 minutes of ischemia also resulted in significantly more apoptosis in cardiac tissue. Kramer and colleagues have shown that renal ischemic injury leads to an increase in pulmonary vascular permeability defects that are mediated through macrophages. Imai and coworkers have demonstrated the role of lung injury in inducing renal damage. They found that in rabbits, injurious lung ventilatory strategies (high tidal volume and low peak end-expiratory pressure) alone were sufficient to induce renal epithelial cell apoptosis. These cytokines result in renal inflammation in kidney transplants from brain-dead donors, distinct from living or cardiac-death donors. Similarly, contralateral kidneys had impaired pressure natriuresis and hemodynamic responses, but reductions in vascular density were observed in the contralateral kidney. The risk for intravascular volume depletion is increased in comatose, sedated, or obtunded patients and in patients with restricted access to salt and water. Findings suggestive of volume depletion on physical examination may include orthostatic hypotension (postural fall in diastolic blood pressure greater than 10 mm Hg) and tachycardia (postural increase in heart rate greater than 10 beats/min), reduced jugular venous pressure, diminished skin turgor, dry mucous membranes, and the absence of axillary sweat. However, overt signs and symptoms of hypovolemia do not usually manifest until extracellular fluid volume has fallen by more than 10% to 20%. In addition, in patients with heart failure or liver disease, renal hypoperfusion may be present despite total body volume overload. Findings on physical examination of peripheral edema, pulmonary vascular congestion, pleural effusion, cardiomegaly, gallop rhythms, elevated jugular venous pressure, or hepatic congestion may point to a state of reduced cardiac output and decreased effective intravascular volume. The presence of acute or chronic liver disease is suggested by evidence of icterus, ascites, splenomegaly, palmar erythema, telangiectasia, and caput medusae. In select critically ill patients, invasive hemodynamic monitoring using central venous or pulmonary artery catheters or ultrasonography of the heart and central veins may assist in assessing intravascular volume status. In patients with underlying systolic heart failure, restoration of renal perfusion may be difficult and may require the use of inotropic support. Flank pain may be a prominent symptom of acute renal artery or renal vein occlusion, acute pyelonephritis, and rarely necrotizing glomerulonephritis. Ophthalmologic examination is useful to assess for signs of atheroembolism; hypertensive or diabetic retinopathy; the keratitis, uveitis, and iritis of autoimmune vasculitides; icterus; and the rare but nevertheless pathognomonic band keratopathy of hypercalcemia and flecked retina of hyperoxalemia. Cardiovascular assessment may reveal marked elevation in systemic blood pressure, suggesting malignant hypertension or scleroderma, or demonstrate a new arrhythmia or murmur, suggesting a potential source of thromboemboli or subacute bacterial endocarditis (acute glomerulonephritis), respectively. Abdominal pain and nausea are frequent clinical correlates of atheroembolic disease, commonly in patients who have recently undergone angiographic evaluation, particularly in the presence of widespread atheromatous disease. While anuria will be seen in complete obstruction, urine volume may be normal or even increased in the setting of partial obstruction. A pattern of fluctuating urine output may also be seen in some patients with partial obstruction. Suprapubic or flank pain may be the presenting complaint if there is acute distension of the bladder or renal collecting system and capsule, respectively. Colicky flank pain radiating to the groin suggests acute ureteral obstruction, most commonly from renal stone disease. Prostatic disease should be suspected in older men with a history of nocturia, urinary frequency, urgency, or hesitancy and an enlarged prostate on rectal examination. Urinary retention may be exacerbated acutely in such patients by medications with anticholinergic properties, such as antihistamine agents and antidepressants. Neurogenic bladder is a likely diagnosis in patients with spinal cord injury or autonomic insufficiency and should be suspected in patients with long-standing diabetes mellitus. Bladder distension may be evident on abdominal percussion and palpation in patients with bladder neck or urethral obstruction. Anuria can be seen with complete urinary tract obstruction but can also be seen with severe prerenal or intrinsic renal disease. Patients with partial urinary tract obstruction may present with polyuria caused by secondary impairment of urinary concentrating mechanisms.

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