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257 Renal Functional Reserve and Microalbuminuria in Offspring of Hypertensive Parents Beatriz Grunfeld, Eduardo Perelstein, Rosa Simsolo, Maria Gimenez, and Juan C. Romero Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017 Renal functional reserve, microalbuminuria, and plasma atrial natriuretic factor were measured in 21 offspring (9.5±0.5 years of age, mean±SEM) of hypertensive parents and in eight children (10±0.5 years of age) with no family history of hypertension who were used as a control group. Renal functional reserve was evaluated by measurement of the changes in creatinine clearance after an oral protein load of 45 g/m2. Atrial natriuretic factor levels were determined before and 60 minutes after the protein load, and microalbuminuria in fractional urine before and 120 minutes after the same stimulus as well as in a 24-hour urine collection. All children in the control group significantly increased their creatinine clearance after the protein load (preload, 122±12; 60 minutes, 144±9; 120 minutes, 154±11; 180 minutes, 144±9 ml/min/1.73 m2; all values were significant vs. preload, p< 0.005). In contrast, only 13 of 21 offspring of hypertensive parents increased their creatinine clearance to values within 2 SD of the increase shown by the control group (preload, 144±11; 60 minutes, 153 ±7; 120 minutes, 202±13 ml/min/1.73 m2;/?<0.001 vs. preload; 180 minutes, 214±19 ml/min/1.73 m2, p<0.001 vs. preload). The remaining eight offspring of hypertensive parents showed no detectable changes (nonresponders) (preload, 189±18; 60 minutes, 146±11; 120 minutes, 170±14; 180 minutes, 168±13 ml/min/1.73 m2; all values p=NS). No changes in atrial natriuretic factor after the protein load were observed in any group. Offspring of hypertensive parents presented higher microalbuminuria levels in 24-hour urine specimens (3.1 /tg/min, tolerance factor [TF]2.2) than controls (2.1 /ig/mln, TF 1.5) (j?<0.05). Although microalbuminuria increased significantly after the water load in the control group (/?<0.05) and in the offspring of hypertensive parents (/><0.01), it returned to baseline at 120 minutes in the former but not in the latter (p<0.05 vs. baseline). The lack of renal functional reserve in nonresponders was significantly related (p<0.05) to the presence of higher levels of microalbuminuria. We conclude that the absence of renal functional reserve and increased microalbuminuria in some normotensive children who are offspring of essential hypertensive parents can indicate that subtle alterations in renal function may precede the onset of clinical hypertension. {Hypertension 1990;15:257-261) S everal lines of evidence suggest that a genetic factor is involved in the pathogenesis of essential hypertension in some patients.1-2 A number of past observations supports the hypothesis that inherited abnormalities in kidney function may participate in the pathogenesis of essential hypertension.3-5 From the Hipertension Arterial, Hospital de Niflos "Ricardo Gutierrez" (B.G., R.S.), the Department of Nephrology, Hospital de Niflos "Ricardo Gutierrez" (E.P.), Buenos Aires, Argentina, the Pediatric Clinical Chemistry Laboratory Hospital Italiano (M.G.), Buenos Aires, Argentina, and the Department of Physiology and Biophysics, Mayo Clinic (J.C.R.), Rochester, Minnesota. Partially supported by grant HL-16496 from the National Institutes of Health. Address for reprints: Dr. J.C. Romero, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Received May 25,1989; accepted in revised form November 24, 1989. We have reported decreased active and inactive urinary kallikrein excretion after a diuretic stimulus in a subgroup of normotensive offspring of essential hypertensive parents as well as in normotensive children with a single kidney.6 As urinary kallikrein has been proposed as an indicator of distal tubular mass or function,7 our findings could be interpreted as an expression of a diminished functional renal mass in the normotensive offspring of hypertensive parents. To gather additional information on their renal function, we evaluated the renal functional reserve (as indicated by the increase in the creatinine clearance after an oral protein load) and the microalbuniin excretion in a group of normotensive children who are offspring of essential hypertensive parents. Oral protein load has been shown to increase glomer- 258 Hypertension Vol 15, No 3, March 1990 TABLE 1. Basal Blood Pressure at the Beginning of the Study N-EH Control Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017 Patient no. Sex Age (yr) BP (mm Hg) Control no. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. F F M F M M M F M F M F M M F M M M F F F 6 12 14 7 14 12 7 5 7 10 13 11 9 13 8 9 14 5 9 11 6 100/68 108/70 116/70 104/64 120/80 118/70 1. 2. 3. 4. 5. 6. 7. 8. Mean± SEM 110/60 104/50 110/60 110/70 122/70 114/72 112/62 120/70 110/70 112/70 120/80 106/66 110/70 110/70 90/64 111/68 Sex F M M F F M M M Age(yr) BP (mm Hg) 10 9 11 8 11 10 11 12 90/60 108/60 115/65 100/70 90/60 114/70 114/72 118/70 Mean± 106/66 SEM 4/2 2/1 N-EH, nonnotensive children with a single hypertensive parent; BP, blood pressure. ular filtration rate in healthy subjects.8 Because atrial natriuretic factor (ANF) has been reported to increase the glomerular nitration rate,9 we also measured plasma fluctuations of ANF after the oral protein load. Methods Patient Population Twenty-one nonnotensive children (N-EH) with a single essential hypertensive parent (11 boys, mean age 9.5 ±0.5 years) and eight nonnotensive children without a family history of essential hypertension (C) (five boys, mean age 10 ±0.5 years) who were attending the Outpatients Clinic at Children's Hospital were included in the study. Children were considered nonnotensive according to the criteria of the Second Task Force on Blood Pressure Control in Children (Table 1). Creatinine clearances (Ccr) were within the normal range in all propositi and none had proteinuria. All subjects were free of medication at the time of the study. All studies were carried out on an outpatient basis. Oral Protein Load Studies were started at 8:00 AM after an overnight fast. After emptying their bladders, the children were given an oral water load of 20 ml/kg body wt, after which two timed 30-minute urine samples were collected by spontaneous voiding; at a midpoint of each 30-minute period, blood was drawn for the creatinine determination from an intravenous butterfly needle introduced into a peripheral arm vein. Baseline Ccr was calculated from the mean value obtained at the two 30-minute periods. The children were then fed an oral protein load (OPL) (lean, cooked hamburger meat) of 45 g/m2 body surface area ingested during a 20-30-minute period. After the meal was completed, three 60-minute urine samples were collected and blood again drawn at the midpoint of each period for Ccr. At the end of each urine collection, an amount of water equivalent to the volume voided was ingested by each child. Blood pressure was taken hourly from the preload period through the third hour of the post-protein load period with a mercury sphygmomanometer. Plasma and urinary creatinine were measured by a standard method by means of an automatic analyzer (Abbott VP Bichromatic Analyzer, Abbott Labs., Dallas, Texas), and Ccr was corrected for body surface and expressed per 1.73 m2. Urinary sodium was measured in the 24-hour urine collection by flame spectrophotometry. Microalbuminuria was measured in three different urine samples: 1) 24-hour urine specimen collected the day before the OPL study; 2) in the second 30-minute urine collection after the water load administered before the protein meal; 3) in the second 60-minute urine collection after the protein load. Urinary urea was also measured in the last two Grunfeld et al TABLE 2. Renal Functional Reserve in Children 259 Creatinine Clearance Values After an Oral Protein Load Postload Group Control N-EH Responders Nonresponders n 8 21 13 8 Basal 143±22 135±8 134±11 136±14 Preload 1 hour 2 hours 122±12 161±11 144±11 189±18|| 144±9* 151±6 153±7 146±11 154±llf 156±18 202±13§ 170±14 3 hours 144±9* 169±21 214±195 168±13 Values are mean±SEM (ml/min/1.73 m2). N-EH, norraotensive offspring of hypertensive parents; basal, values obtained from 24-hour urine collected the day before the study. *p<0.05; :tp<0.01; t.P<0.005; §p<0.001 when compared with respective preload values. ip<0.01 when compared with N-EH responders. Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017 samples. Microalbuminuria was measured by radioimmunoassay with the method of Miles et al,10 as modified in our laboratory. The first antibody was purchased from Serotec (Oxfordshire, UK). Standards for iodination and standard curves were from Calbiochem (Calbiochem Corp., La Jolla, California) catalogue No. 126658 and 126654, respectively. Interassay variation coefficient was 15% and 13%, respectively, and the sensitivity was 7.8 ng. ANF was measured by radioimmunoassay in three different plasma samples: 1) in basal conditions before the water load, 2) 1 hour after the water load and before the protein meal, and 3) 1 hour after the protein load. Plasma levels of ANF were measured with the method of Gutkowska et al.11 The antibody against ANF-(99-126) was kindly supplied by Y. Gutkowska, who also helped us set up the assay in our laboratory. All the other reactions were obtained from Peninsula Labs., Inc., Belmont, California. Parental consent for the present study was obtained after giving appropriate information in all cases. Statistical Methods Statistical analysis of the results was done by nonparametric methods because changes in Ccr after the protein load, as well as microalbuminuria, may not follow a normal distribution, as stated by other authors. The Wilcoxon signed rank test was used to evaluate changes in Ccr after the protein load within each group. The median test was applied to study the differences among the groups. Fisher's exact test on two-by-two contingency tables were used to determine a possible relation between the response to the protein load and microalbuminuria. Results are expressed as mean±SEM, except for microalbuminuria; which is expressed antilogged with a geometric mean (GM) equivalent to the arithmetic mean of the logged data, and a tolerance factor (TF) equivalent to the standard deviation of the logged data, except that the GM is multiplied or divided by the TF. Results were considered statistically significant whenp<0.05. Results Creatinine clearance values obtained after the oral protein load are shown in Table 2. Although the Ccr in the children in the control group increased significantly after the protein load (p<0.005), no significant changes in the mean Ccr were recorded in the N-EH group children. However, when the results obtained in the latter group were analyzed in a more discriminative manner, two subsets of children could be identified: 13 of 21 children in the N-EH group (62%) did in fact increase their Ccr significantly (p<0.001) (responders) to values within 2 SD of the increase shown by the control group, whereas 8 of 21 children in the N-EH group (38%) did not (nonresponders) (Figure 1). No significant changes in blood pressure were recorded throughout the study. Basal urinary urea excretion was similar in N-EH responders and nonresponders, and it increased significantly after the protein load (responders: basal 13.4±9 g and post-protein load 16.3±1.2 g,p<0.01; nonresponders: basal 10.7±1.7 g and post-protein Ioadl8.2±2.5g, j p<0.01). Urinary sodium excretion was similar in the N-EH responder and nonresponder groups, and it was not different from the control groups (responders, 98 ±17 meq/24 hr; nonresponders, 94 ±20 meq/24 hr; and C, 110±23 meq/24 hr). Basal plasma ANF levels were similar in control and N-EH children, and they showed no signficant changes either after the water load or after the protein load (C: basal 107±10 pg/ml, after water load 98±18 pg/ml, and after protein load 94±5 pg/ml; N-EH: basal 111±47 pg/ml, after water load 118±46 pg/ml, and after protein load 124±67 pg/ml). Microalbuminuria in the 24-hour urine collection was higher in a total population of 33 N-EH than in CONTROLS PRE POST PRE POST FIGURE 1. Graph showing creatinine clearance response to an oral protein load. N-EH, normotenswe offspring of hypertensive parents; full lines, responders; dotted lines, nonresponders. 260 Hypertension Vol 15, No 3, March 1990 motensive when transplanted with a kidney donated from a normotensive rat3-4 lent support for the theory on the primacy of the kidney in the pathogenesis of essential hypertension. A dramatic reversal of hypertension has also been reported in some patients with end-stage renal disease after successful renal transplantation.12'13 Thus, a number of past observations support the contention that something in the kidney may be primarily at fault, in at least a subset of essential hypertensive patients. Healthy subjects have been shown to increase their glomerular filtration rate after a meat meal, and this increase has been considered a measure of the renal Basal PruWntaad functional reserve. Patients with renal disease have a Oonbo) lack of renal functional reserve, and the presence of FIGURE 2. Graph showing microalbuminuria response to an glomerular hyperfiltration in the remnant nephrons oral protein load. N-EH, normotensive offspring of hyperten- has been postulated as the underlying mechanism. sive parents. *p<0.05; **p<0.01 vs. respective baseline. Further support for the latter comes from experimental data demonstrating an increase in single nephron glomerular nitration rate of the remnant 20 appropriate control subjects (N-EH: 3.1 ^g/min, nephrons after renal ablation.14 TF 2.2; C: 2.1 jig/min, TF 1.5;/J<0.05). Microalbuminuria increased significantly 1 hour after the water Our present finding of a lack of renal functional load in the 21 N-EH (p<0.01) and in the eight reserve in a subset of normotensive offspring of control subjects (p<0.05) included in the study (Nessential hypertensive patients, together with our EH: 12.1, TF 2.6; C: 8.8, TF 1.9 fig/min). Although past observation of a decreased urinary kallikrein microalbuminuria decreased 2 hours after the protein excretion in both the N-EH and normotensive single load in both groups, the N-EH group had not returned kidney children,6 lend additional support to our to baseline whereas the control group did (N-EH: 8.2, hypothesis that a diminished functional renal mass is TF 1.6 ng/min, p<0.05 vs. baseline; C: 4.3, TF 1.7 present in a subset of normotensive children who are jtg/min) (Figure 2). The lack of Ccr response to the offspring of essential hypertensive parents. protein load in the N-EH children was significantly A primary defect in glomerular development leadrelated (p<0.05) to the presence of high levels of ing to a reduction in single nephron filtration rate microalbuminuria (>mean 2 TF of control group). (probably due to a lower glomerular hydraulic conductivity or surface area) was described in Milan Discussion hypertensive strain rats, an animal model for essential hypertension.15 Based on these data, it may be Our results indicate that the creatinine clearance speculated that hypofiltration rather than hyperfiltraresponse to an oral protein load was significantly tion could have led to the lack of renal functional altered in 38% of a cohort of N-EH children, sugreserve found in some of our patients. gesting that some of these children may have an abnormal renal functional reserve in spite of having Vascular structural changes before the developshown normal renal function by standard diagnostic ment of hypertension have been reported in spontatests. In addition, N-EH children presented signifineously hypertensive rats.16 An inappropriate vascucantly increased mean microalbumin excretion when lar constrictory state has recently been postulated to compared with control subjects without a family be present in offspring of essential hypertensive history of essential hypertension. Furthermore, a parents.17 Therefore, structural or functional vascusignificant relation between the lack of renal funclar alterations, or both, may be mediators of the lack tional reserve and increased microalbuminuria was of response to the meat meal. also found in these children. Differences in dietary protein intake or in the absorption of the meat meal could be ruled out as We used the endogenous creatinine clearance as responsible for our findings as 24-hour urinary urea an estimation of the glomerular nitration rate, as was similar in all children studied and urea excretion other authors have previously shown that creatinine after the protein load increased comparably in both clearance and inulin clearance rendered similar responder and nonresponder N-EH groups. results in this test.8 Although it has long been known that both clearances may be discordant because of A restricted sodium diet cannot be related to the tubular secretion of creatinine, this discrepancy lack of creatinine clearance either, as the urinary becomes important only when the glomerular filtrasodium excretion was again similar in both N-EH tion rate is decreased. Differences between both subgroups.18 clearances have previously been reported to be less Our findings do not support a role for ANF in than 10% in subjects with normal renal function. mediating the creatinine clearance response to an The observation that bilaterally nephrectomized oral protein load. The increased microalbuminuria spontaneously hypertensive rats will become norfound in N-EH children could have been the result of mtarodbumkulii (ug/mln) Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017 Grunfeld et al Renal Functional Reserve in Children early alterations in the glomerular capillary permeability secondary to glomerular hemodynamic abnormalities, as previously suggested.19 The above speculation is furthered by our observation of a significant relation between the absence of renal functional reserve and microalbumin excretion in the N-EH group. In synthesis, the absence of renal functional reserve and increased microalbuminuria in some normotensive children who are offspring of essential hypertensive parents, indicate that subtle alterations in renal function may precede the onset of clinical hypertension. Long-term follow-up of these children may contribute to the understanding of the pathophysiological meaning of the findings here reported and presumably establish their possible usefulness for the identification of children at risk for developing essential hypertension. Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017 References 1. Bianchi G, Cusi D, Barlassina C, Lupi P, Ferrari P, Picotti G, Gatti M, Polli E: Renal dysfunction as a possible cause of essential hypertension in predisposed subjects. Kidney Int 1983;23:870-875 2. Platt R: Heredity in hypertension. Lancet 1963;l:899-904 3. Bianchi G, Fox U, DiFrancesco GF, Giovanetti AM, Pagetti D: Blood pressure changes produced by kidney crosstransplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med 1974;47:435-448 4. Dahl LK, Heine M: Primary role of renal homografts in setting chronic blood pressure levels in rats. Ore Res 1975;36:692-696 5. Guyton AC: Arterial Pressure and Hypertension. Philadelphia, WB Saunders Co, 1980, pp 457-569 6. Grunfeld B, Gimenez M, Simsolo R, Becu L: Kalikrina urinaria total y activa en ninos hipertensos y en ninos con rinon unico (abstract). Mcdicina 1987;47:571 7. Spragg J, Denney DL, Tilney NL, Austen KF: Kallikrein excretion in renal transplant recipients and in uninephrectomized donors. Kidney Int 1985;28:75-81 261 8. Bosch JP, Sacaggi A, Lauer A, Ronco C, Belledonne M, Glabman S: Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate. Am J Med 1983; 75:943-950 9. Ortola FV, Ballermann BJ, Anderson S, Mendez RE, Brenner BM: Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. / Clin Invest 1984;80:670, 674 10. Miles D, Mogensen C, Gundersen H: Radioimmunoassay for urinary albumin using a single antibody. Scand J Clin Lab Invest 1970;26:511-514 11. Gutkowska J, Bourassa M, Roy D, Thibault G, Garcia R, Contin N, Genest J: Immunoreactive atrial natriuretic factor (ir-ANF) in human plasma. Btochem Biophys Res Commun 1985;128:1350-1356 12. Rao TKS, Gupta SK, Butt KMH, Kauntz SL, Friedman EA: Relationship of renal transplantation to hypertension in end stage renal failure. Arch Intern Med 1978;138:1236-1241 13. Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel JD, Jones P, Diethelm AG: Remission of essential hypertension after renal transplantation. NEnglJMed 1983^09:1009-1015 14. Ayslett JP: Functional adaptation to reduction in renal mass. Physiol Rev 1979^59:137-164 15. Baer PG, Bianchi G: Renal micropuncrure study of normotensive and Milan hypertensive rats before and after development of hypertension. Kidney Int 1978;13:452-466 16. Eccleston-Joyner CA, Gray SD: Arterial hypertrophy in the fetal and neonatal spontaneously hypertensive rat. Hypertension 1988;12:513-518 17. Blackshear JL, Garnic D, Williams GH, Harrington DP, Hollenberg NK: Exaggerated renal vasodilator response to calcium entry blockade in first-degree relatives of essential hypertensive subjects. Hypertension 1987;9:384-389 18. Ruilope L, Rodicio J, Garcia Robles R, Sancho J, Miranda B, Granger J, Romero JC: Influence of a low sodium diet on the renal response to aminoacid infusions in humans. Kidney Int 1987;31:992-999 19. Hostetter TH, Olson JL, Rennke HG, Venkachatalam MA, Brenner BM: Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. Am J Physiol 1981; 241-.F85-F93 KEY WORDS • family history microalbuminuria renal function atrial natriuretic factor Renal functional reserve and microalbuminuria in offspring of hypertensive parents. B Grunfeld, E Perelstein, R Simsolo, M Gimenez and J C Romero Hypertension. 1990;15:257-261 doi: 10.1161/01.HYP.15.3.257 Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. 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