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Renal acid excretion in patients with hypogammaglobulinemia
CLINICA CHIMICA ACTA
CC‘45299
RENAL
ACID
EXCRETION
IN PATIENTS
WITH
HYPOGAMMAGLOBULINEMIA
ICHIRO
RIATSUDA,
NAOYOSHI
Depavtment
of Pediatrics,
(Received
July 13, 1972)
Hokkaido
SHIDX,
‘L’XUO
University
T,kKEKOSHI,
School of Medicine,
ANU NAOKI
FUKUSHIMA
Sappovo (Japan)
SUMMARY
Renal
acidification
was tested
by an ammonium
chloride
load in hypo- and
hypergammaglobulinemic patients. Urinary bicarbonate excretion was studied on hypogammaglobulinemic patients. The results obtained suggest that levels of serum y-globulins have no direct effect on urinary acid excretion.
Many reports have been published on renal tubular acidosis associated with hypergammaglobulinemia, such as Sjogren’s syndrome 1,2, idiopathic hyperglobulinemial, hyperglobulinemic purpura3 and lupoid hepatiti9. To our knowledge, urinary acid excretion in patients with hypogammaglobulinemia has not been studied, although it might give useful evidence for determining whether the gammaglobulin level has a direct effect on renal acidification. This paper described urinary acid excretion in patients with hypo- and hypergammaglobulinemia. METHOD AND MATERIAL
Three patients with Bruton type hypogammaglobulinemia and 6 patients with hypergammaglobulinemia were studied (Table I). Ten normal children between 4-14 years with body surface areas between 0.60-1.42 m2 were used as control. All subjects had normal glomerular filtration rate, endogenous creatinine clearance, (more than 70 ml/min/r.73 m2) and maximal urinary osmolarity, exceeding 700 mOsm/kg after overnight fluid deprivation. Serum sodium and potassium levels were normal in all subjects. test For the present study, we chose the short test of urinary acidification by Wrong and Davis5 rather than that by Edelman et al.“, since this method was used in many studies of hypergammaglobulinemic renal acidosis hitherto reported2,3$11 and was found to be suitable for measuring the acid excretion in children also’. At 8 a.m. the bladder was emptied and thereafter 2-hourly urine collections were obtained until 6 p.m., without catheterization. Urine specimens were stored under mineral oil below 5” during the test and analysed immediately. Ammonium chloride
Acid excretion
Clin. Chim. Acta, 42
(1972)
241-24~
MATSUDA et d.
242 TABLE
I
PCO, mm/Hg
HCO,
39.2 43.0 39.0
22.6 24.6 21.0
wquivll
Uiagnosis
_ 2
3 II
nr M
3
9
iv
4 5
12 I2
F
6 7 8
5 ‘4 I2
M F F
9
I2
M
I
I;
5 19 5
26
83.2 130.0 112.5
7.39 7.39 7.35
198 196 180
*40 226 260
6500 4800
10.5.X IO9.I
34.0
21.8
2700
IOS.0
21-l 82
6500 2jOO
70.5 I0,j.j
7.42 7.43 7.48 7.40 7.44
37.5 39.5 40.0 39.0
25.0 24.6 21.6 22.4
870 994 420
140
1560
121.0
7.4’
40.0
22.0
1231
70~120
7.33-7.4.5
40.0
LO-2-j
14 5
4s II0 5
Hypogamma@obulinemia Hypogammaglobulinemia Hypo~amma~lobulinemia Idiopathic Hypergammaglobulinemia Chronic hepatitis liheumatoid arthritis Chronic nephritis Hypergammaglobulinemic Purpura Chronic infection
Control 4-14
163
+9o
123
x&36
ztt4*o
g/kg was administered orally, sometimes through gastric tube, after one control collection of urine. The pH and carbon dioxide content of the blood were measured at 38” with an Astrup micro-equipment. Measurement of urinary pH was made with a Horiba pH meter, Model P at room temperature. Titratable acid in urine was measured by titration at room temperature and pH 7.7. Ammonium was measured by the micro-diffusion method of ConwayS. The carbon dioxide tension in urine (P+) was directly determined by the Tatebe gas analyzer, and bicarbonate concentration was calculated from the Henderson-Hassel-
0.1
balch equation. IqFuencc of carboxic anhydrase inhibitor Acetazolamide (Diamox) was employed as carbonic anhydrase inhibitor. At 8 a.m. the bladder was emptied, thereafter at IO a.m., z p.m., 6 p.m., IO pm. and IO a.m. the next morning urine samples were collected, and stored under mineral oil below o” during the test. Diamox 5 mg/kg was given orally, after one control collection of urine. Urinary pH and bicarbonate content were measured by the methods described above. RESULT
Ah‘D COMMEKT
Shortly after ammonium chloride loading urine pH was decreased to 5.4 or less in control subjects and excretion of titratable acid and ammonium increased as urine pH decreased. The excretion rates of ammonium and titratable acid in hypogammaglobulinemic patients, in response to acid loading, were similar to those of the control patients (Fig. I). In order to study the action of carbonic anhydrase inhibitor on renal function, Diamox was administered to IO control children and to 3 patients with hypogammaglobulinemia. This medication was immediately followed by a marked increase in bicarbonate and urine pH, in all cases (Fig. 2). There was also no difference in the rates of bicarbonate excretion and in the changes of urine pH between the control patients and the hypogammaglobulinemic patients indicating that the amount of Clin. Chim. k!Cta, 42 (rg72)
241-244
RENAL
ACID
EXCRETION
IN HYPERGAMMAGLOBULINEMIA
243
1c
1c T.A.mEq 42 5
7 PH 6
0
2
4
6
8Hr
02
6
10
22 Hr
Fig. 1. Urinary pH and rates of excretion of titratable acid and ammonium ion after administration of ammonium chloride (0.1 g/kg) in hypogammaglobulinemic patients. The values of titratable acid and ammonium ion represent cumulative excretion during the observed period. Shaded area indicates normal range. Fig. 2. Urinary pH and rates of excretion of bicarbonate after administration (5 mg/kg) in hypogammaglobulinemic patients. Shaded area indicates normal
Diamox used had a similar activity
in suppressing
urinary acidification
of Xcetazolamide range.
in both groups.
These results suggest that a low level of serum gammaglobulin per se did not enhance urinary acid excretion. Although the urine pH values of all patients with hypergammaglobulinemia used in the present study were within the normal range (Fig. 3), acid excretion, especially as ammonium ion, was impaired in 3 of 6 patients (cases No. 5, 7, 8), while the other 3 patients had normal renal acid excretion. Among the patients with impaired acid excretion, case Ko. 7 had cryoproteinemia and evidence of renal damage, such as haematuria and mild proliferative changes of the glomerulis, a sign of chronic glomerular nephritis having an immunological basis. Case No. 8 suffered from hypergammaglobulinemic purpura and cryoproteinemia, and could be classified as a subclinical type of renal tubular acidosis, since there were no symptoms referable to renal tubular acidosis in the present stage. It has been proposed9 that in some cases of hypergammaglobulinemic purpura the paraprotein is filtered through the glomeruli and subsequently being reabsorbed in the proximal tubular cells, causes tubular damage. Recently Pasternak and Linder lo found special antibodies reacting with renal tubular antigens in patients with renal tubular acidosis in whom the serum Clin. Chiw
Acta, q2
(1972)
241-241
MATSUDA
244
t?tal.
10
T.A. mEq /
PH
m2 5
7, 6.
, 0
2
4
6
8 Hr
Fig. 3. Urinary pH and rates of excretion of titratable acid (T.A.) and ammonium ion after administration of ammonium chloride (0.1 g/kg) in hypergammaglobulinemic patients. The values of. titratable acid and ammonium ion represent cumulative excretion during the observed period. Shaded arc indicates normal range.
y-globulin level was normal. They considered that autoimmunity was involved in the pathogenesis of renal tubular acidosis in some cases. Since no relationship between renal tubular acidosis and the degree of hypergammaglobulinemia has been established’l and, as evidenced in the present study, the levels in serum y-globulins have no direct effect on urinary acid excretion, the presence of paraprotein or a specific antibody for renal tubular cells in the patient’s serum may play a role in the occurrence of impaired renal tubular acidification. total
I 2 3 ; 5 6 7 8 9 IO II
K. C. MOORIS, JR. AND H. H. FUUESBERC, ~Tfedicinr, 46 (1967) 57, N. TALAL, E. ZISMAK AND P. I~. SCHUR, Arthritis ~hwwzt., II (1968) 774 .I. CHOE~ AK;U R. J. W.~Y, Austv. Ann. :ZIed., II (1962) 189. 11. I<. READ, S. %&LOCK AND C. V. HARRISOX, Gut, ‘1 (1963) 37X. 0. WROKC AND H. E. F. DAVIS, C)u&. 1. Mczd., 28 (19j9) 259. C. M. EDBLMAK, JR., C. 31. DIOCH~S, JR., J. RODRIQUEZ-SORIAKO, AND H. STARK, Pcdiat.
Kes..
I (1967) .+jz. 1. MATSUDA, T. TAKEUA ASD N. SHIDA, Clin. Chim. ‘ilcta, 20 (1968) 37. E. J. CONwAY, Microdiffusion Analysis and Tiolumetric Error, McMillan, New 1-ork, 1952. D. CONSTAXZA AND M. M. SWALLER, Anzev. J. Med., 31 (1963) 125. X. PASTERNAK AND E. LIPSIIER, Clin. Exfi. Immuwol., 7 (1970) IIS. -4. I’ASTERSAK, J. MARTIO, Xl. NISSILA ASD 0. WEGELIS, Actn Med. Stand., 187 (1970) 123.
CC‘45299
RENAL
ACID
EXCRETION
IN PATIENTS
WITH
HYPOGAMMAGLOBULINEMIA
ICHIRO
RIATSUDA,
NAOYOSHI
Depavtment
of Pediatrics,
(Received
July 13, 1972)
Hokkaido
SHIDX,
‘L’XUO
University
T,kKEKOSHI,
School of Medicine,
ANU NAOKI
FUKUSHIMA
Sappovo (Japan)
SUMMARY
Renal
acidification
was tested
by an ammonium
chloride
load in hypo- and
hypergammaglobulinemic patients. Urinary bicarbonate excretion was studied on hypogammaglobulinemic patients. The results obtained suggest that levels of serum y-globulins have no direct effect on urinary acid excretion.
Many reports have been published on renal tubular acidosis associated with hypergammaglobulinemia, such as Sjogren’s syndrome 1,2, idiopathic hyperglobulinemial, hyperglobulinemic purpura3 and lupoid hepatiti9. To our knowledge, urinary acid excretion in patients with hypogammaglobulinemia has not been studied, although it might give useful evidence for determining whether the gammaglobulin level has a direct effect on renal acidification. This paper described urinary acid excretion in patients with hypo- and hypergammaglobulinemia. METHOD AND MATERIAL
Three patients with Bruton type hypogammaglobulinemia and 6 patients with hypergammaglobulinemia were studied (Table I). Ten normal children between 4-14 years with body surface areas between 0.60-1.42 m2 were used as control. All subjects had normal glomerular filtration rate, endogenous creatinine clearance, (more than 70 ml/min/r.73 m2) and maximal urinary osmolarity, exceeding 700 mOsm/kg after overnight fluid deprivation. Serum sodium and potassium levels were normal in all subjects. test For the present study, we chose the short test of urinary acidification by Wrong and Davis5 rather than that by Edelman et al.“, since this method was used in many studies of hypergammaglobulinemic renal acidosis hitherto reported2,3$11 and was found to be suitable for measuring the acid excretion in children also’. At 8 a.m. the bladder was emptied and thereafter 2-hourly urine collections were obtained until 6 p.m., without catheterization. Urine specimens were stored under mineral oil below 5” during the test and analysed immediately. Ammonium chloride
Acid excretion
Clin. Chim. Acta, 42
(1972)
241-24~
MATSUDA et d.
242 TABLE
I
PCO, mm/Hg
HCO,
39.2 43.0 39.0
22.6 24.6 21.0
wquivll
Uiagnosis
_ 2
3 II
nr M
3
9
iv
4 5
12 I2
F
6 7 8
5 ‘4 I2
M F F
9
I2
M
I
I;
5 19 5
26
83.2 130.0 112.5
7.39 7.39 7.35
198 196 180
*40 226 260
6500 4800
10.5.X IO9.I
34.0
21.8
2700
IOS.0
21-l 82
6500 2jOO
70.5 I0,j.j
7.42 7.43 7.48 7.40 7.44
37.5 39.5 40.0 39.0
25.0 24.6 21.6 22.4
870 994 420
140
1560
121.0
7.4’
40.0
22.0
1231
70~120
7.33-7.4.5
40.0
LO-2-j
14 5
4s II0 5
Hypogamma@obulinemia Hypogammaglobulinemia Hypo~amma~lobulinemia Idiopathic Hypergammaglobulinemia Chronic hepatitis liheumatoid arthritis Chronic nephritis Hypergammaglobulinemic Purpura Chronic infection
Control 4-14
163
+9o
123
x&36
ztt4*o
g/kg was administered orally, sometimes through gastric tube, after one control collection of urine. The pH and carbon dioxide content of the blood were measured at 38” with an Astrup micro-equipment. Measurement of urinary pH was made with a Horiba pH meter, Model P at room temperature. Titratable acid in urine was measured by titration at room temperature and pH 7.7. Ammonium was measured by the micro-diffusion method of ConwayS. The carbon dioxide tension in urine (P+) was directly determined by the Tatebe gas analyzer, and bicarbonate concentration was calculated from the Henderson-Hassel-
0.1
balch equation. IqFuencc of carboxic anhydrase inhibitor Acetazolamide (Diamox) was employed as carbonic anhydrase inhibitor. At 8 a.m. the bladder was emptied, thereafter at IO a.m., z p.m., 6 p.m., IO pm. and IO a.m. the next morning urine samples were collected, and stored under mineral oil below o” during the test. Diamox 5 mg/kg was given orally, after one control collection of urine. Urinary pH and bicarbonate content were measured by the methods described above. RESULT
Ah‘D COMMEKT
Shortly after ammonium chloride loading urine pH was decreased to 5.4 or less in control subjects and excretion of titratable acid and ammonium increased as urine pH decreased. The excretion rates of ammonium and titratable acid in hypogammaglobulinemic patients, in response to acid loading, were similar to those of the control patients (Fig. I). In order to study the action of carbonic anhydrase inhibitor on renal function, Diamox was administered to IO control children and to 3 patients with hypogammaglobulinemia. This medication was immediately followed by a marked increase in bicarbonate and urine pH, in all cases (Fig. 2). There was also no difference in the rates of bicarbonate excretion and in the changes of urine pH between the control patients and the hypogammaglobulinemic patients indicating that the amount of Clin. Chim. k!Cta, 42 (rg72)
241-244
RENAL
ACID
EXCRETION
IN HYPERGAMMAGLOBULINEMIA
243
1c
1c T.A.mEq 42 5
7 PH 6
0
2
4
6
8Hr
02
6
10
22 Hr
Fig. 1. Urinary pH and rates of excretion of titratable acid and ammonium ion after administration of ammonium chloride (0.1 g/kg) in hypogammaglobulinemic patients. The values of titratable acid and ammonium ion represent cumulative excretion during the observed period. Shaded area indicates normal range. Fig. 2. Urinary pH and rates of excretion of bicarbonate after administration (5 mg/kg) in hypogammaglobulinemic patients. Shaded area indicates normal
Diamox used had a similar activity
in suppressing
urinary acidification
of Xcetazolamide range.
in both groups.
These results suggest that a low level of serum gammaglobulin per se did not enhance urinary acid excretion. Although the urine pH values of all patients with hypergammaglobulinemia used in the present study were within the normal range (Fig. 3), acid excretion, especially as ammonium ion, was impaired in 3 of 6 patients (cases No. 5, 7, 8), while the other 3 patients had normal renal acid excretion. Among the patients with impaired acid excretion, case Ko. 7 had cryoproteinemia and evidence of renal damage, such as haematuria and mild proliferative changes of the glomerulis, a sign of chronic glomerular nephritis having an immunological basis. Case No. 8 suffered from hypergammaglobulinemic purpura and cryoproteinemia, and could be classified as a subclinical type of renal tubular acidosis, since there were no symptoms referable to renal tubular acidosis in the present stage. It has been proposed9 that in some cases of hypergammaglobulinemic purpura the paraprotein is filtered through the glomeruli and subsequently being reabsorbed in the proximal tubular cells, causes tubular damage. Recently Pasternak and Linder lo found special antibodies reacting with renal tubular antigens in patients with renal tubular acidosis in whom the serum Clin. Chiw
Acta, q2
(1972)
241-241
MATSUDA
244
t?tal.
10
T.A. mEq /
PH
m2 5
7, 6.
, 0
2
4
6
8 Hr
Fig. 3. Urinary pH and rates of excretion of titratable acid (T.A.) and ammonium ion after administration of ammonium chloride (0.1 g/kg) in hypergammaglobulinemic patients. The values of. titratable acid and ammonium ion represent cumulative excretion during the observed period. Shaded arc indicates normal range.
y-globulin level was normal. They considered that autoimmunity was involved in the pathogenesis of renal tubular acidosis in some cases. Since no relationship between renal tubular acidosis and the degree of hypergammaglobulinemia has been established’l and, as evidenced in the present study, the levels in serum y-globulins have no direct effect on urinary acid excretion, the presence of paraprotein or a specific antibody for renal tubular cells in the patient’s serum may play a role in the occurrence of impaired renal tubular acidification. total
I 2 3 ; 5 6 7 8 9 IO II
K. C. MOORIS, JR. AND H. H. FUUESBERC, ~Tfedicinr, 46 (1967) 57, N. TALAL, E. ZISMAK AND P. I~. SCHUR, Arthritis ~hwwzt., II (1968) 774 .I. CHOE~ AK;U R. J. W.~Y, Austv. Ann. :ZIed., II (1962) 189. 11. I<. READ, S. %&LOCK AND C. V. HARRISOX, Gut, ‘1 (1963) 37X. 0. WROKC AND H. E. F. DAVIS, C)u&. 1. Mczd., 28 (19j9) 259. C. M. EDBLMAK, JR., C. 31. DIOCH~S, JR., J. RODRIQUEZ-SORIAKO, AND H. STARK, Pcdiat.
Kes..
I (1967) .+jz. 1. MATSUDA, T. TAKEUA ASD N. SHIDA, Clin. Chim. ‘ilcta, 20 (1968) 37. E. J. CONwAY, Microdiffusion Analysis and Tiolumetric Error, McMillan, New 1-ork, 1952. D. CONSTAXZA AND M. M. SWALLER, Anzev. J. Med., 31 (1963) 125. X. PASTERNAK AND E. LIPSIIER, Clin. Exfi. Immuwol., 7 (1970) IIS. -4. I’ASTERSAK, J. MARTIO, Xl. NISSILA ASD 0. WEGELIS, Actn Med. Stand., 187 (1970) 123.