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Urinary Concentrating Defect in Experimental Hemochromatosis1 Urinary Concentrating Defect in Experimental Hemochromatosis1 X.J. Zhou, N.D. Vaziri,2 D. Pandian, Z.Q. Wang, M. Mazowiecki, S.Y. Liao, and F. Oveisi ulation carry the gene for and 1% actually suffer from X.J. Zhou. ND. Vaziri, D. Pandian, Z.Q. Wang, M. iron overload (1). Tissue iron overload without tissue Mazowiecki, S.Y. Liao, F. Oveisi Division of Nephrology, damage, usually referred to as hemosiderosis or sid- Department of Medicine, University of California, Ir- erosis, may occur as a result of redistribution of iron vine, CA in such organs as the lungs, kidneys, or liver with little or no increase in total body iron content. The term (J. Am. Soc. Nephrol. 1996; 7:128-134) hemochromatosis is used to denote chronic iron over- load leading to tissue damage. From the etiological standpoint, hemochromatosis is classified into pri- ABSTRACT mary and secondary types. Primary hemochromatosis We studied the urinary concentrating capacity in is caused by an autosomal recessive disorder of intes- experimental hemochromatosis. Sprague-Dawley tinal iron transport, whereas secondary hemochroma- rats were randomized into iron (Fe)-loaded (injected tosis is the result of other causes of excess iron sc with 1.2 g elemental iron/kg body weight as iron burden. dextran) and pair-fed control groups. The urinary Hemochromatosis is associated with a variety of concentrating ability was studied after 10 months of clinical disorders including hepatic cirrhosis (2,3), iron loading. At basal condition, urine osmolality cardiac involvement (2.4.5). various endocrinopathies (e.g., diabetes mellitus, hypothyroidism, hypopara- (Uosm) was significantly lower (P < 0.05) in the Fe- thyroidism, hypogonadism) (3,6-8), skin hyperpig- loaded rats compared with the control animals de- mentation, certain neoplasms (9,10), and impaired spite comparable urinary arginine-vasopressin (AVP) cellular immunity (11). Surprisingly, the available excretion in the two groups. Although 48-h water information on the effect of iron overload on renal deprivation resulted in comparable rises in plasma structure and function is quite limited. In a recent concentration and urinary excretion of AVP in the two study (12), acute iron overload was shown to have no groups, maximal Uosm in the Fe-loaded animals was demonstrable deleterious effect on kidney despite in- significantly lower than that seen in the control group creased lipid peroxidation. In another study, Master- (P < 0.01). Moreover, the observed urinary concen- angelo et al. (13) reported urinary concentrating defect trating defect could not be corrected by pharmaco- in a group of ten patients with thalassemia and pro- logical doses of exogenous AVP. There was no signif- longed iron-overload syndrome as a result of repeated blood transfusions. However, the mechanism of the icant difference in renal chloride, sodium, calcium, or reported defect was not clearly defined. Rats treated magnesium handling at either basal or sodium de- with iron dextran have been previously employed as pleted states. Histologic studies showed marked iron an experimental model of secondary hemochromato- deposition in the cortex and outer medulla accom- sis (14). The study presented here was designed to panied by mild tubular atrophy particularly in the examine the effect of iron dextran-induced hemochro- distal convoluted tubules. Thus, chronic experimental matosis on urinary concentrating capacity in rats. iron overload leads to nephrogenic diabetes insipi- dus marked by AVP-resistant urinary concentrating METHODS defect. Animals Key Words: Iron overload, vasopressin. osmolallty, hemosider- Male Sprague-Dawley rats (Charles River Inc., Wilmington. osis, renal sodium handling MA) weighing 340 to 380 g were randomIzed into iron- dextran (Fe) loaded and control groups. Animals placed in A lthough iron is an essential element for nearly all the Fe-loaded group received a single sc injection of an living organisms. its excessive accumulation can iron-dextran complex (Sigma Chemical Co., St. Louis, MO) at lead to severe cellular injury and organ damage. Until a dose of 1.2 g elemental iron/kg body weight and were recently, the true prevalence of iron overload in the allowed free access to food (Purina Rat Chow, Purina Mills, general population was not fully appreciated. It is now St. Louis, MO) and water. The dosage of iron employed here was based on the previously published studies (15,16) of rats known that approximately 10% of the American pop- with iron dextran-induced hemochromatosis. Animals as- signed to the control group received injections of the vehicle 1 Received September 27. 1994. Accepted September 1. 1995. alone and were pair-fed with their Fe-loaded counterparts. 2Correspondence to Dr. N.D. Vozirl, Division of Nephroiogy, Department of Pair-feeding was accomplished by limiting the amount of Medicine. uci Medical Center, 101 The City Drive. Orange. CA 92668-4088. food available to each control animal to that consumed 1046-6673/070 1.0 128503.00/0 Journal of the American Society of Nephroiogy during the preceding 24 h by its Fe-loaded counterpart. Copyright © 1996 by the American Society of Nephrology Animals were kept for 10 months in a university animal 128 Volume 7 - Number 1 1996 Zhou et a) research facility. Arterial blood pressure was monitored by mm. to replace fluid losses during surgery. A 0.2- mL ahlquot using a rat- tail sphygmomanometer (Harvard Apparatus, of blood was then collected as blank, and 1.5 mL saline South Natick. MA). At the end of the 10-month observation containing inulin (20 gIL). sodium para-aminohippurate period, animals were placed in individual metabolic cages. (PAH, 15 g/L) and D-mannltol (30 g/L) was given as Iv bolus, Twenty-four-hour urine collection was obtained for the mea- followed by a sustained infusion at a rate of 3.9 mL/h. After surements of total volume and osmolailty. An ahiquot of urine a 90-min equilibration period, urine was collected under oil was adjusted to pH 4.5 with acetic acid and frozen at -70#{176}C for 30 min, and arterial blood samples were obtained at the for AVP determination. Blood was drawn from the orbital midpoint of the urine collection. Samples were used for the sinus for the measurements of hematocrit and osmolallty. measurements of inuhin and PAH clearances. The choice of a 10-month observation period was made on In addition, renal handling of chloride, sodium, calcium, the basis of the preliminary experiments, which showed no and magnesium was tested in five rats in each group. The significant difference between the two groups In urine vol- rats were placed in individual metabolic cages and 24-h ume or osmolailty at either basal or dehydrated condItions urine samples were collected. They were then subjected to after 4 months of iron-dextran admInistration (Table 1). salt depletion as follows. In brief, after two daily injections of Therefore, we extended the observations for an additional 6 furosemlde (10 mg/kg, ip), the rats were placed exclusively months. on a sodium-deficient diet (ICN Biomedicals. Inc., Cleveland, OH) for 7 days. The rats were given tap water ad Ilbitum. At Maximum Concentrating Ability the end of this period, 24-h urine samples were collected and urinary sodium, chloride, calcium, and magnesium were Ten rats in each group were placed in individual metabolic measured by standard laboratory techniques. Blood was also cages and allowed free access to food and water for 24 h. This drawn from the orbital sinus for the measurements of elec- was followed by a 48-h period during which water was trolytes. withheld. Immediately after the first 24-h water deprivation cycle, a micro-osmotic pump (Aiza Corporation, Palo Alto. CA) was implanted subcutaneously and was set to deliver a AVP Measurements synthetic AVP preparation at a continuous rate of 2.0 U/kg Plasma and urine AVP were measured by RIA using re- per 24 h. At the end of the experiments, the micro-osmotic agents obtained from Nichols Institute Diagnostics Inc. (San pumps were removed. The experIments were repeated 1 wk Juan Capistrano, CA). AVP was extracted from plasma sam- later without AVP infusion. Urine samples were collected ples with bentonite and assayed by the method of Skowsky et under oil during each experimental period, and urine volume al. (18) In a typical assay, 1 mL of plasma was extracted with was recorded. The samples were then stored at - 70#{176}Cforthe bentonite (3 mg). and the AVP bound to the bentonite was measurements of AVP and osmolailty. Blood was drawn eluted by using acidified acetone. The eluate was dried under Immediately after the 48-h water deprivation period for de- nitrogen. The AVP-contalning residue was reconstituted and termination of AVP and osmolahity. The choice of 48-h water assayed by RIA. In the RIA, an aliquot of the reconstituted deprivation was based on the observation of Bankir and material was mixed with rabbit antl-AVP and incubated for DeRouffignac (17), who showed that maxImal urinary con- 72 h at 4#{176}C.1125k] AVP was added and the incubation was centration may not be reached before 48 h in rats. continued for another 24 h. Bound/free separation was achieved by using a second antIbody (goat antirabbit -y Clearance Experiments globulin). Standard clearance experiments were performed as fol- For urine AVP measurement, the urine sample was ex- lows. Animals were anesthetized with an intraperitoneal tracted (1 mL) by usIng Sep-pak columns (Waters Inc., Injection of sodium pentobarbltal (50 mg/kg) and placed on a Milforb, MA). Sep-pak-bound AVP was eluted with acidified heating pad to maintain the body temperature at 37#{176}C.The acetonltrlle. The eluate was dried under nitrogen and recon- jugular vein, carotid artery, and the bladder were then stituted for RIA.
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