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Hypercalciuria and hematuria in non-insulin-dependent diabetes mellitus
Hypercalciuria and Hematuria in Non-Insulin-Dependent Diabetes Mellitus
Yasuko Chiba Naoko Arakawa Nagayuki Tani Hiroshi Nakamura Takeshi Momotsu Seiki Ito Akira Shibata
ABSTRACT
The First Department of Internal Medicine, Nigata University School of Medicine, Nigata, Japan
This study was undertaken to examine whether patients with noninsulin-dependent diabetes (NIDDM) are hypercalciuric and whether there is a pathophysiologic relationship between urinary calcium excretion (UCE) and the degree of diabetic nephropathy. Although UCE did not parallel the increase of urinary albumin excretion rate (AER) and the presence of hematuria was not corrected with the degree of UCE, we confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients with normo- or microalbuminuria than in the controls. In 6 months, the AER of two hypercalciuric patients increased. However, the blood pressure and HbA,, of these two patients increased during the same 6 months. Therefore, it remains unclear whether hypercalciuria induced an increase in the AER of these patients. (The Journal of Diabetic Complications 5;2-3:150-152, 1991.)
INTRODUCTION Several investigators reported that diabetic patients have an increased urinary calcium excretion (UCE)le3 and that hypercalciuria may contribute to the exacerbation of diabetic nephropathy due to nephrocalcinosis.’ In addition, an increased prevalence of hypercalciuria in diabetic children with hematuria4 and the existence of glomerular hematuria related to hypercalciuria in diabetic patients with severe proteinuria5 were reported. Therefore this study was undertaken to elucidate whether patients with non-insulin-dependent diabetes mellitus (NIDDM) were hypercalciuric and whether there was a relationship between the UCE, hematuria, and the degree of diabetic nephropathy.
SUBJECTS AND METHODS
Reprint requests to be sent to: Yasuko Chiba, First Department of Internal Medicine, Niigata University School of Medicine, l-754 Asahinachidori, Niigata 951, Japan.
0 1991 Elsevier Science Publishing 0891-6632/91/$3.50
150
Co., Inc.
Timed overnight urine samples (n = 256) without urinary infection from 193 outpatients with NIDDM whose serum creatinine levels were below 1.1 mg/dL and samples (n = 14) from healthy subjects were examined. Measurement of urinary calcium was carried out by the OCPC method and albumin, by the latex agglutination test. A good reproducibility of the urinary calcium and albumin was confirmed. Results were expressed as a calcium-creatinine ratio (mg Calg Cre) and urinary albumin excretion rate (AER, kg/min), respectively. The degree of diabetic nephropathy was evaluated by AER. Hematuria was defined as the presence of more than 5 erythrocytes per high-power field in the sediment as seen by light microscopy. Statistical analysis was undertaken using Student’s t test.
RESULTS First, the UCE was compared between diabetic patients and the control subjects. Diabetic patients had a wide range of UCE. The mean (? standard error [SE]) was 194.0 ? 7.84, which was significantly higher
151
HYPERCALCIURIAAND HEMATURIA IN NIDDM
Calcium ma/&r0
mean + SE. DM
: 194.0 f 7.84
Control
600
:
94.6 f
15.0
p < 0.01
92/256
500
of hematuria was 2% in patients with hypercalciuria and 3% in patients without hypercalciuria. There was no correlation between UCE and hematuria. The AER of patients with hematuria varied a great deal and there was no significant difference between the AER of patients with hematuria and those without hematuria.
(36 %I
DISCUSSION 400
300
mean + 2SD _-_, I
200
100
0
DM
Control
FIG. 7 This graph shows urinary calcium excretion in diabetic patients (OM) and the controls. The mean (+ standard error[SE]) of the urinary calcium excretion in diabetic patients was 194.0 k 7.84 mg CaYg Cre, which was significantly higher than that of the controls (94.6 k 15.0 mg C&g Cre). The dotted line represents mean 1 2 standard deviations (SD) considered as the normal upper limit of calcium excretion. Thirty-six percent of diabetic patients had urinary calcium excretion of more than 270 mg Ca/g Cre.
We confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients than in control subjects. Among diabetic patients, UCE was significantly greater in normo- and microalbuminuric patients than in macroalbuminuric ones. Malone et al. reported that hypercalciuria may play a previously unrecognized role in the progression of diabetic nephropathy.’ This report, together with our findings, led us to consider that hypercalciuria might play some role in the progression of diabetic nephropathy without macroalbuminuria. It has been reported that there is a causal relationship between increased UCE and hematuria.4-” In this study, there was no correlation between UCE and hematuria. This discrepancy may be explained by two possibilities: One is that only patients with normal creatinine levels were selected and the other is that the number of patients with
Calcium mg/gCre +
patients
with
hematuria 600
500
than that of the controls (Figure 1). Hypercalciuria was considered to be present when UCE was beyond mean 22 standard deviations (SD) of the normal controls (210 mg Calg Cre). According to this criterion, 36% of diabetic patients had hypercalciuria. It was clear that hypercalciuria was more frequent in diabetic patients than in the healthy controls. Secondly, the relationship between UCE and AER was examined. The means of UCE in diabetics with different degrees of AER (normo, 120 figi min; micro, 20 to 200 pgimin; macro, 2200 pg/min) were 185.9 k 8.3 mgCa/gCre, 227.1 2 19.0 mgCa/gCre, and 148.9 ? 52.6 mgCa/gCre, respectively. There was no significant relationship between UCE and AER. Thirdly, the progression of diabetic nephropathy during a half-year period was examined in diabetic patients with hypercalciuria. In this study, AER of two hypercalciuric patients increased in a half-year. But in these two patients, the levels of HbA,, and mean blood pressure also increased. Therefore, a possibility existed that progression of AER was influenced by increased blood pressure and the blood sugar level. Fourthly, the correlation between UCE and hematuria was examined (Figure 2). The frequency
400
f i* : H (+)
300
2/92
t_-
200
-----. .
100
(2%)
H (+) 5/164
(3%)
i
0
DM
Co&r01
FIG. 2 The levels of urinary calcium excretion in diabetic patients (DM) with hematuria. The seven arrows in the figure represent the values for urinary calcium excretion of the patients with hematuria. The frequency of hematuria was 2% in patients with hypercalciuria and 3% in patients without hypercalciuria.
152
DISCUSSION We confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients than in control subjects. Among diabetic patients, UCE was significantly greater in normo- and microalbuminuric patients than in macroalbuminuric ones. Malone et al. reported that hypercalciuria may play a previously unrecognized role in the progression of diabetic nephropathy.’ This report, together with our findings, led us to consider that hypercalciuria might play some role in the progression of diabetic nephropathy without macroalbuminuria. It has been reported that there is a causal relationship between increased UCE and hematuria.4-6 In this study, there was no correlation between UCE and hematuria. This discrepancy may be explained by two possibilities: One is that only patients with normal creatinine levels were selected and the other is that the number of patients with hematuria was too small in our study. Although Lopes et al. reported that 30% of diabetic patients without clinical nephropathy had microscopic hematuria,5 we did not recognize the presence of a causal relationship between he-
CHIBA ET AL.
maturia and the degree of AER. This discrepancy findings may be explained by the same possibilities tioned above.
in the men-
REFERENCES 1. Malone JI, Lowitt S, Duncan JA, Shah SC: Hematuria and hypercalciuria in children with diabetes mellitus. Pediatrics
?9:756-759, 1987. 2. Malone JI, Lowitt S, Duncan JA, Shah SC, Vargas A, Root AW: Hypercalciuria, hyperphosphaturia, and growth retardation in children with diabetes mellitus. Pediatrics 78:298303, 1986. 3. lshihara M, Shinoda T, Yamada T: Co-occurrence of hypercalciuria and hypouricaemia in type-2 diabetic patients. Diabetic Med 6:406-411, 1989. 4. Steplen FB, Stapleton FB, Roy S Ill, Noe HN, Jerkins G: Hypercalciuria in children with hematuria. N Engl J Med 310:1345-1348, 1984. 5. Lopes JB, Moura LAR, Lopes SR, Ramos OL, Pereira AB: Glomerular hematuria in diabetics. C/in Nephrol 30:117-121, 1988. 6. Kalia A, Travis LB, Brouhard BH: The association of idiopathic hypercalciuria and asymptomatic gross hematuria in children. Pediatrics 99:716-719, 1981.
Yasuko Chiba Naoko Arakawa Nagayuki Tani Hiroshi Nakamura Takeshi Momotsu Seiki Ito Akira Shibata
ABSTRACT
The First Department of Internal Medicine, Nigata University School of Medicine, Nigata, Japan
This study was undertaken to examine whether patients with noninsulin-dependent diabetes (NIDDM) are hypercalciuric and whether there is a pathophysiologic relationship between urinary calcium excretion (UCE) and the degree of diabetic nephropathy. Although UCE did not parallel the increase of urinary albumin excretion rate (AER) and the presence of hematuria was not corrected with the degree of UCE, we confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients with normo- or microalbuminuria than in the controls. In 6 months, the AER of two hypercalciuric patients increased. However, the blood pressure and HbA,, of these two patients increased during the same 6 months. Therefore, it remains unclear whether hypercalciuria induced an increase in the AER of these patients. (The Journal of Diabetic Complications 5;2-3:150-152, 1991.)
INTRODUCTION Several investigators reported that diabetic patients have an increased urinary calcium excretion (UCE)le3 and that hypercalciuria may contribute to the exacerbation of diabetic nephropathy due to nephrocalcinosis.’ In addition, an increased prevalence of hypercalciuria in diabetic children with hematuria4 and the existence of glomerular hematuria related to hypercalciuria in diabetic patients with severe proteinuria5 were reported. Therefore this study was undertaken to elucidate whether patients with non-insulin-dependent diabetes mellitus (NIDDM) were hypercalciuric and whether there was a relationship between the UCE, hematuria, and the degree of diabetic nephropathy.
SUBJECTS AND METHODS
Reprint requests to be sent to: Yasuko Chiba, First Department of Internal Medicine, Niigata University School of Medicine, l-754 Asahinachidori, Niigata 951, Japan.
0 1991 Elsevier Science Publishing 0891-6632/91/$3.50
150
Co., Inc.
Timed overnight urine samples (n = 256) without urinary infection from 193 outpatients with NIDDM whose serum creatinine levels were below 1.1 mg/dL and samples (n = 14) from healthy subjects were examined. Measurement of urinary calcium was carried out by the OCPC method and albumin, by the latex agglutination test. A good reproducibility of the urinary calcium and albumin was confirmed. Results were expressed as a calcium-creatinine ratio (mg Calg Cre) and urinary albumin excretion rate (AER, kg/min), respectively. The degree of diabetic nephropathy was evaluated by AER. Hematuria was defined as the presence of more than 5 erythrocytes per high-power field in the sediment as seen by light microscopy. Statistical analysis was undertaken using Student’s t test.
RESULTS First, the UCE was compared between diabetic patients and the control subjects. Diabetic patients had a wide range of UCE. The mean (? standard error [SE]) was 194.0 ? 7.84, which was significantly higher
151
HYPERCALCIURIAAND HEMATURIA IN NIDDM
Calcium ma/&r0
mean + SE. DM
: 194.0 f 7.84
Control
600
:
94.6 f
15.0
p < 0.01
92/256
500
of hematuria was 2% in patients with hypercalciuria and 3% in patients without hypercalciuria. There was no correlation between UCE and hematuria. The AER of patients with hematuria varied a great deal and there was no significant difference between the AER of patients with hematuria and those without hematuria.
(36 %I
DISCUSSION 400
300
mean + 2SD _-_, I
200
100
0
DM
Control
FIG. 7 This graph shows urinary calcium excretion in diabetic patients (OM) and the controls. The mean (+ standard error[SE]) of the urinary calcium excretion in diabetic patients was 194.0 k 7.84 mg CaYg Cre, which was significantly higher than that of the controls (94.6 k 15.0 mg C&g Cre). The dotted line represents mean 1 2 standard deviations (SD) considered as the normal upper limit of calcium excretion. Thirty-six percent of diabetic patients had urinary calcium excretion of more than 270 mg Ca/g Cre.
We confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients than in control subjects. Among diabetic patients, UCE was significantly greater in normo- and microalbuminuric patients than in macroalbuminuric ones. Malone et al. reported that hypercalciuria may play a previously unrecognized role in the progression of diabetic nephropathy.’ This report, together with our findings, led us to consider that hypercalciuria might play some role in the progression of diabetic nephropathy without macroalbuminuria. It has been reported that there is a causal relationship between increased UCE and hematuria.4-” In this study, there was no correlation between UCE and hematuria. This discrepancy may be explained by two possibilities: One is that only patients with normal creatinine levels were selected and the other is that the number of patients with
Calcium mg/gCre +
patients
with
hematuria 600
500
than that of the controls (Figure 1). Hypercalciuria was considered to be present when UCE was beyond mean 22 standard deviations (SD) of the normal controls (210 mg Calg Cre). According to this criterion, 36% of diabetic patients had hypercalciuria. It was clear that hypercalciuria was more frequent in diabetic patients than in the healthy controls. Secondly, the relationship between UCE and AER was examined. The means of UCE in diabetics with different degrees of AER (normo, 120 figi min; micro, 20 to 200 pgimin; macro, 2200 pg/min) were 185.9 k 8.3 mgCa/gCre, 227.1 2 19.0 mgCa/gCre, and 148.9 ? 52.6 mgCa/gCre, respectively. There was no significant relationship between UCE and AER. Thirdly, the progression of diabetic nephropathy during a half-year period was examined in diabetic patients with hypercalciuria. In this study, AER of two hypercalciuric patients increased in a half-year. But in these two patients, the levels of HbA,, and mean blood pressure also increased. Therefore, a possibility existed that progression of AER was influenced by increased blood pressure and the blood sugar level. Fourthly, the correlation between UCE and hematuria was examined (Figure 2). The frequency
400
f i* : H (+)
300
2/92
t_-
200
-----. .
100
(2%)
H (+) 5/164
(3%)
i
0
DM
Co&r01
FIG. 2 The levels of urinary calcium excretion in diabetic patients (DM) with hematuria. The seven arrows in the figure represent the values for urinary calcium excretion of the patients with hematuria. The frequency of hematuria was 2% in patients with hypercalciuria and 3% in patients without hypercalciuria.
152
DISCUSSION We confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients than in control subjects. Among diabetic patients, UCE was significantly greater in normo- and microalbuminuric patients than in macroalbuminuric ones. Malone et al. reported that hypercalciuria may play a previously unrecognized role in the progression of diabetic nephropathy.’ This report, together with our findings, led us to consider that hypercalciuria might play some role in the progression of diabetic nephropathy without macroalbuminuria. It has been reported that there is a causal relationship between increased UCE and hematuria.4-6 In this study, there was no correlation between UCE and hematuria. This discrepancy may be explained by two possibilities: One is that only patients with normal creatinine levels were selected and the other is that the number of patients with hematuria was too small in our study. Although Lopes et al. reported that 30% of diabetic patients without clinical nephropathy had microscopic hematuria,5 we did not recognize the presence of a causal relationship between he-
CHIBA ET AL.
maturia and the degree of AER. This discrepancy findings may be explained by the same possibilities tioned above.
in the men-
REFERENCES 1. Malone JI, Lowitt S, Duncan JA, Shah SC: Hematuria and hypercalciuria in children with diabetes mellitus. Pediatrics
?9:756-759, 1987. 2. Malone JI, Lowitt S, Duncan JA, Shah SC, Vargas A, Root AW: Hypercalciuria, hyperphosphaturia, and growth retardation in children with diabetes mellitus. Pediatrics 78:298303, 1986. 3. lshihara M, Shinoda T, Yamada T: Co-occurrence of hypercalciuria and hypouricaemia in type-2 diabetic patients. Diabetic Med 6:406-411, 1989. 4. Steplen FB, Stapleton FB, Roy S Ill, Noe HN, Jerkins G: Hypercalciuria in children with hematuria. N Engl J Med 310:1345-1348, 1984. 5. Lopes JB, Moura LAR, Lopes SR, Ramos OL, Pereira AB: Glomerular hematuria in diabetics. C/in Nephrol 30:117-121, 1988. 6. Kalia A, Travis LB, Brouhard BH: The association of idiopathic hypercalciuria and asymptomatic gross hematuria in children. Pediatrics 99:716-719, 1981.