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*
The Second Department of Internal Medicine, Tohoku University School of
Medicine, Sendai, Japan
Department of Nephrology, Sendai Shakaihoken Hospital, Sendai,
Japan.
Correspondence to Dr. Jun Soma, The Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, 980-8574, Japan. Phone: +81 22 717 7163; Fax: +81 22 717 7168; E-mail: sjun2i{at}mail.cc.tohoku.ac.jp
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In Japan, the prevalence of hepatitis C virus (HCV) antibody among blood donors is about 0.6% in the general population, but it increases with age, reaching 1 to 2% in the fifth and sixth decades of life (9). Interestingly, a high prevalence of HCV infection was recently reported in diabetic patients (10,11). In our experience, patients positive for HCV antibody with diabetic glomerulosclerosis may rapidly progress to end-stage renal failure and need hemodialysis. To date, however, there has been no study of the significance of HCV infection in diabetic nephropathy. We speculated that HCV infection may have an adverse effect on the progression of diabetic nephropathy. Recently, the decline in renal function of patients with cryoglobulinemic or membranous glomerulonephritis has been reported to be faster among patients with HCV infection compared to those without HCV infection (12,13). In the present study, therefore, we retrospectively investigated whether HCV infection affects the prognosis of diabetic nephropathy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2.0), moderate (2.0 < II-DGS index 3.0), and advanced (3.0 <
II-DGS index 4.0) (17).
The degree of periodic acid-Schiff-positive arteriolar hyalinosis was
semiquantitatively graded as absent, mild, moderate, or severe. First, we investigated the prevalence of HCV infection in each renal disease among the 2370 patients. Some cases in which II-DGS and primary renal diseases coexisted were classified into the II-DGS group. The patients diagnosed as II-DGS were divided into two groups based on whether they had HCV antibody (HCV-positive group) or not (HCV-negative group). Then, clinical parameters at renal biopsy such as age, gender, serum creatinine, urinary protein excretion, hematuria, HbA1c, BP, the percentages of insulin-treated patients and those with diabetic retinopathy, duration of diabetes, liver function, and antihypertensive drugs, as well as the histologic parameters mentioned above, were compared between the two groups. Cirrhosis was diagnosed when we morphologically confirmed findings characteristic of cirrhosis on computed tomographic scanning or ultrasonography in patients who showed findings such as spider angiomata, palmar erythema, a firm and nontender liver, abnormal collateral veins on the abdomen, a decrease in cholinesterase, thrombocytopenia, leukocytopenia, elevations of thymol and zinc sulfate turbidity, and abnormalities of coagulation test. Hematuria was defined as red blood cells >4/high-powered field in urinary sediments. Duration of diabetes indicated a period between the initial diagnosis of diabetes and biopsy. HCV RNA in the serum was examined by reverse transcription (RT)-PCR with primers derived from the 5' noncoding highly conserved region of the HCV genome (18) or branched DNA probe assay, which has been developed by Chiron Corp. (Emeryville, CA) (19). At the same time, follow-up study after renal biopsy was done in both groups. The decline in renal function was evaluated for each patient on the basis of the slope in reciprocal serum creatinine (1/SCr) over time (20,21). The need for hemodialysis or death from nonrenal disease during conservatively managed renal failure was considered the end point. Antihypertensive drugs at the final follow-up were also examined. The final data of follow-up study were obtained in January 1999. Additionally, apart from these biopsied patients, we randomly examined HCV antibody in outpatients and inpatients who had type II diabetes mellitus and were not under hemodialysis in our hospital (n = 545). Then clinical and laboratory findings were compared between HCV-positive and -negative patients, as in the study of biopsied patients, except urinary protein, which was examined by a urine dipstick.
Previous blood transfusions, previous surgical procedures, and the presence of a tattoo were examined in both biopsied and nonbiopsied patients as risk factors for HCV infection.
Statistical Analyses
All values are expressed as mean ± SD. Statistical analyses were
performed using an unpaired t test, 
2 test, or
Mann-Whitney U test, where appropriate. The renal survival was
calculated for HCV-positive and -negative II-DGS groups by Kaplan-Meier
analysis, and the log-rank test was used to assess the difference in the
survival curves. We also used a multiple linear regression analysis with SAS
REG procedure (22), where we
treated 1/SCr slope as a dependent variable. Age, gender, BP,
urinary protein excretion, HbA1c, the presence of HCV antibody, index of
II-DGS, and the degree of arteriolar hyalinosis were defined as independent
variables. We converted four parameters into dummy variables: for gender being
female as 0, male as 1; for HCV antibody being negative as 0, positive as 1;
for index of II-DGS being mild and moderate as 0, advanced as 1; and for
arteriolar hyalinosis being absent, mild, and moderate as 0, and severe as 1.
The other parameters were used as continuous variables. P < 0.05
was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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II-DGS in Patients Who Were Not Tested for HCV Antibody
In 1273 biopsied patients who were not tested for HCV antibody, 39 had
II-DGS. The prevalence of II-DGS was significantly higher (P = 0.003)
in HCV-tested patients (123 of 2370; 5.2%) than in non-tested patients (39 of
1273; 3.1%). The mean age was significantly higher in 2370 HCV-tested patients
than in 1273 non-tested patients (43.4 ± 18.7 versus 34.2
± 21.9 yr; P < 0.0001), and the number of patients younger
than 18 yr old was significantly lower (P < 0.0001) in HCV-tested
patients (289 of 2370; 12.2%) than in non-tested patients (475 of 1273;
37.3%).
Clinical and Laboratory Findings of Patients with II-DGS at Renal
Biopsy
At renal biopsy, age, BP, serum creatinine, HbA1c, urinary protein
excretion, the percentages of insulin-treated patients and those with diabetic
retinopathy, and duration of diabetes were comparable between the HCV-positive
and -negative groups (Table 2).
The number of patients who showed hematuria tended to be larger in the
HCV-positive group than in the HCV-negative group, but the difference was not
significant (11 of 24 versus 27 of 99; P = 0.078). The
male-to-female ratio in the HCV-positive group was significantly greater than
that in the HCV-negative group (M/F: 22/2 versus 61/39, respectively;
P = 0.004). Both aspartate aminotransferase and alanine
aminotransferase concentrations were significantly higher in the HCV-positive
group than in the HCV-negative group (P < 0.0001), and the
cholinesterase concentration was significantly lower in the former group than
in the latter (P < 0.0001). Four patients had cirrhosis in the
HCV-positive group, but none had the disease in the HCV-negative group. HCV
RNA in the serum was examined in 12 patients by branched DNA probe assay and
in four by RT-PCR. In all, 12 patients had detectable HCV RNA in the serum (12
of 16; 75%): nine of 12 by branched DNA probe assay and three of four by
RT-PCR.
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As risk factors for HCV infection, previous blood transfusions were recognized in eight male and two female patients (10 of 24; 41.7%), previous surgical procedures in 15 male patients (15 of 24; 62.5%), and a tattoo in one male patient (1 of 24; 4.2%) who had no history of transfusion or surgical procedure.
Antihypertensive Drugs in Patients with II-DGS
Table 3 shows the number of
patients who took each antihypertensive drug. At the time of renal biopsy,
angiotensin-converting enzyme inhibitors (ACEI) were more frequently used in
the HCV-positive group (20 of 24; 83.3%) than in the HCV-negative group (55 of
99; 55.6%), and the difference was significant (P = 0.012). However,
calcium antagonists (CaA) and other antihypertensive drugs such as adrenergic
inhibitors and diuretics were equally used in both groups. Angiotensin II
receptor antagonists (AIIA) were not used in any case. There were 0 and 7
patients who took no antihypertensive drugs in the HCV-positive and -negative
groups, respectively, but the difference was not significant. At the final
follow-up, ACEI, CaA, and other drugs were used equally in both groups. AIIA
was used in one case of the HCV-positive group and in three of the
HCV-negative group, but the difference was not significant. There also was no
difference in the percentage of patients who took no antihypertensive drugs
between the two groups.
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Histologic Findings of Patients with II-DGS
Histologically, the index of II-DGS and the degree of arteriolar hyalinosis
were comparable between the two groups
(Table 4). In 24 HCV-positive
II-DGS patients, MPGN was also present in three patients
(Figure 1), IgA nephropathy
(IgAN) in two, and membranous nephropathy (MN) in one. In 99 HCV-negative
II-DGS patients, IgAN was present in six patients and MN in three. Primary
renal diseases were identified in more patients of the HCV-positive group (6
of 24; 25.0%) than in the HCV-negative group (9 of 99; 9.1%), and this
difference was significant (P = 0.033).
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Follow-Up Study of Patients with II-DGS
The follow-up period after renal biopsy was 4 to 59 mo (23.7 ± 14.2)
in the HCV-positive group and 5 to 58 mo (28.7 ± 12.9) in the
HCV-negative group (Table 5).
This difference was not significant. During conservatively managed renal
failure, three patients of the HCV-positive group and five patients of the
HCV-negative group died from nonrenal diseases such as acute myocardial
infarction, lung cancer, pneumonia, and sepsis. Hemodialysis was newly
introduced in more of the HCV-positive group (8 of 24; 33.3%) than in the
HCV-negative group (18 of 99; 18.2%), but this difference was not significant
(P = 0.103). However, patients in the HCV-positive group showed a
faster deterioration in renal function measured by 1/SCr compared
with those in the HCV-negative group (-0.30 ± 0.27 dl/mg per yr
versus -0.14 ± 0.19 dl/mg per yr, respectively; P =
0.001). When we did a follow-up study excluding the patients with MPGN, MN, or
cirrhosis in both groups, the decline in renal function reflected by
1/SCr was also significantly greater in the HCV-positive group than
in the HCV-negative group (-0.22 ± 0.15 dl/mg per yr versus
-0.14 ± 0.19 dl/mg per yr; P = 0.048; data not shown)
(Table 5).
Figure 2 shows Kaplan-Meier
renal survival curves excluding the patients who died from nonrenal disease
during conservatively managed renal failure. The log-rank test performed on
the survival curves showed that the difference between the two groups was
significant (P = 0.019). When the patients who died from nonrenal
disease during conservatively managed renal failure were censored as of date
of death, the log-rank test on renal survival curves also showed significant
difference between the two groups (P = 0.035; data not shown).
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Association between HCV Infection and Decline of Renal Function of
II-DGS
The above bivariate association between HCV infection and 1/SCr
slope was further examined by a multivariate analysis.
Table 6 shows a multiple
regression of the decline in renal function of II-DGS on HCV infection and
other variables, as indicated by a multiple linear regression analysis.
Urinary protein excretion, severe arteriolar hyalinosis, and HCV infection
were significantly associated with the decline in renal function indicated by
1/SCr. The result shows that 1/SCr slope in HCV-positive
II-DGS patients was steeper excessively by 0.1828 dl/mg per yr compared with
that in HCV-negative II-DGS patients (95% confidence interval: 0.0869, 0.2787;
P < 0.001).
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HCV Infection in Nonbiopsied Patients with Type II Diabetes
Mellitus
When 545 nonbiopsied patients with type II diabetes mellitus were randomly
examined for HCV antibody (Table
7), 56 patients were found to be positive for HCV antibody (56 of
545; 10.3%). The mean age was higher in HCV-positive patients than in
HCV-negative patients (63.3 ± 10.4 versus 59.6 ± 12.2
yr; P = 0.013). There were no statistical differences between
HCV-positive and -negative patients in the male-to-female ratio, BP, HbA1c,
the percentage of insulin-treated patients, and duration of diabetes. Fundus
examination was done in 53 of 56 HCV-positive patients and in 449 of 489
HCV-negative patients. The percentage of patients with diabetic retinopathy
was comparable in the two groups. The mean of serum creatinine was 0.97
± 0.76 mg/dl in HCV-positive patients and 0.85 ± 0.71 mg/dl in
HCV-negative patients, but this difference was not significant (P =
0.263). Both aspartate aminotransferase and alanine aminotransferase
concentrations were significantly higher in HCV-positive patients than in
HCV-negative patients (P < 0.001 and P = 0.011,
respectively). The cholinesterase concentration was significantly lower in
HCV-positive patients than in HCV-negative patients (P < 0.0001).
Cirrhosis was recognized in 13 cases of HCV-positive patients (13 of 56;
23.2%) and in five of the HCV-negative patients (5 of 489; 1.0%), and the
difference was significant (P < 0.0001). Regarding cirrhosis of
the five HCV-negative patients, the cause was hepatitis B in two patients,
alcoholism in one, and unknown in two. HCV RNA in the serum was examined in
four patients by branched DNA probe assay and in seven by RT-PCR. Of them,
five patients had detectable HCV RNA (5 of 11; 45.5%): one of four by branched
DNA probe assay and four of seven by RT-PCR. Proteinuria as examined by a
urine dipstick was greater in 56 HCV-positive patients than in 497
HCV-negative patients. In 56 HCV-positive patients: - or ±, 28; 1+, 11;
2+, 9; and 3+, 8; and in 489 HCV-negative patients: - or ±, 346; 1+,
59; 2+, 51; and 3+, 33 (HCV-positive versus HCV-negative; P
= 0.001 by Mann-Whitney U test). ACEI, CaA, and other
antihypertensive drugs were used equally in both groups. AIIA were not used in
any case. The percentage of patients who took no antihypertensive drugs was
comparable between the two groups.
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As risk factors for HCV infection, previous blood transfusions were recognized in 24 patients (24 of 56; 42.4%) and previous surgical procedures in 35 (35 of 56; 62.5%). A tattoo was not recognized in any case.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although HCV infection is well known to have an association with MPGN and MN (25,26,27), there has been no study of the prevalence of HCV infection in II-DGS. Accordingly, it is very important that the current study shows the highest prevalence in II-DGS but not in MPGN or MN. This evidence was clarified by the large amount of biopsies from patients with diabetes mellitus and the examination of HCV antibody in many of them for the screening of infectious diseases before renal biopsy. The question in the present study may be whether our study contains a nephrologic selection bias in the indication of renal biopsy. Actually, the prevalence of II-DGS was significantly higher (P = 0.003) in HCV-tested patients (123 of 2370; 5.2%) than in non-tested patients (39 of 1273; 3.1%). However, the mean age of non-tested patients was significantly lower (P < 0.0001) than that of tested patients, and the percentage of patients younger than 18 yr old was significantly larger in non-tested patients than in tested patients (475 of 1273 = 37.3% versus 289 of 2370 = 12.2%; P < 0.0001). Because the prevalence of HCV antibody in schoolchildren in Japan is reported to be 0% (9), HCV antibody is seldom tested in them. In addition, a high prevalence of HCV infection was also identified in nonbiopsied diabetic patients (56 of 545; 10.3%) who were not under hemodialysis. The result is consistent with recent studies from Spain (18 of 176; 11.5%) (10) and Turkey (8 of 100; 8%) (11). These facts and results mitigate the possibility that our study may contain a nephrologic selection bias in the indication for renal biopsy.
Another important aspect of this study is that the degree of proteinuria was greater in HCV-positive patients than in HCV-negative patients. Serum creatinine levels tended to be higher in HCV-positive patients (0.97 ± 0.76 mg/dl) than in HCV-negative patients (0.85 ± 0.71 mg/dl), although the difference was not significant. These results and the association of the degree of proteinuria with the deterioration of renal function (Table 6) emphasize that HCV infection may influence the progression of diabetic nephropathy.
The reason for a high prevalence of HCV infection in diabetic patients is uncertain. Although approximately one-half of the patients had a history of blood transfusions and more than half had a history of surgical procedures, this does not necessarily prove the cause of HCV infection directly. In addition, it would be necessary to investigate the history of intravenous drug addiction. However, we could not investigate it since intravenous drug use is a serious crime in Japan. After all, the cause of HCV infection has been reported to be uncertain in half of Japanese patients with HCV antibody (28). Diabetic patients may be at risk of acquiring HCV infection. However, both Simó et al. (10) and Özyilkan et al. (11) provided some arguments suggesting that this might not be the case, since they did not find differences between HCV-positive and -negative diabetic patients in terms of hospital admissions, previous surgical procedures, mode of treatment, intravenous drug addiction, and previous blood transfusion. Recently, Allison et al. reported a significantly increased rate of diabetes in patients with HCV-related cirrhosis, compared with other causes (29), and hepatitis C has been recognized as a multifaceted disease (30). Therefore, it is possible that HCV infection may play an etiopathologenic role in diabetes, just as HCV infection has been associated etiologically with glomerulonephritis (25,26,27), hypertrophic cardiomyopathy (31), polyarthritis (32), and sicca syndrome (33).
Although we could not comprehensively explain why the renal function of HCV-positive patients with II-DGS rapidly deteriorated, we have some interesting theories. Immune complex glomerulonephritis has been reported to occur at a higher frequency in patients with diabetic nephropathy than in the nondiabetic population (34,35,36). In the current study, coexistence of primary renal diseases with II-DGS was found more frequently in HCV-positive patients (6 of 24; 25.0%) than in HCV-negative patients (9 of 99; 9.1%). Three MPGN cases and one MN case were found in the HCV-positive group, in contrast to the HCV-negative group in which six cases were IgAN and no case was MPGN. Judging from our results and past studies showing a close relationship between HCV infection in MPGN and MN (25,26,27), it is suspected that the associated MPGN and MN in II-DGS may be related to HCV infection. We must bear in mind that associated immunemediated glomerulonephritis in patients with diabetic nephropathy usually displays a rapid progression to renal failure (35,36). In the present study, 1/SCr slopes of one MPGN and one MN patient were great—-0.76 dl/mg per yr and -0.87 dl/mg per yr, respectively—and a patient with MPGN was introduced to hemodialysis only 14 mo after renal biopsy even though the initial serum creatinine was 1.3 mg/dl. Another problem is that four patients with HCV-positive II-DGS had cirrhosis. It is well known that HCV infection causes frequently cirrhosis (37). In cirrhosis, an intense intrarenal vasoconstriction and hypoperfusion contribute to the rapid deterioration of renal function (38). Actually, hemodialysis was introduced in three of the four patients with cirrhosis, in whom 1/SCr slope was -0.63, -0.76, and -0.27 dl/mg per yr, respectively. Thinking of these possible mechanisms of rapid progression of HCV-positive II-DGS, interferon may be indicated to suppress the rapid progression of diabetic nephropathy in some cases with associated immune complex glomerulonephritis, e.g., MPGN/MN, and chronic hepatitis C, since interferon has been reported to be effective in chronic hepatitis C and HCV-associated glomerulonephritis (25,39). Recently, it has been established that the association of interferon plus ribavirin is much more efficient than either of these drugs tested alone with respect to HCV RNA clearance (40,41). There is a possibility that the combination therapy could be one choice of therapies for HCV-positive diabetic nephropathy.
However, the decline in renal function reflected by 1/SCr was also significantly greater in the HCV-positive group than in the HCV-negative group when the patients with MPGN, MN, or cirrhosis were excluded. Therefore, the above-mentioned mechanisms are not enough to explain the rapid progression of HCV-positive II-DGS. As a possible mechanism to link HCV to diabetes, it has been postulated that HCV could infect pancreatic islet cells and thereby directly induce damage to ß cells (10). HCV RNA has been reported to be detected in the heart of patients with hypertrophic cardiomyopathy, and this suggests that HCV may replicate in the heart and could play a role in cardiac hypertrophy (31). Therefore, the possibility that HCV may infect renal tissue, such as mesangial cells, and contribute to renal damage directly cannot be excluded. In the present study, only 75% of II-DGS patients with HCV antibody had detectable HCV RNA. Regarding this point, there is a possibility that if all patients were tested for HCV RNA by RT-PCR, the percentage of patients with detectable HCV RNA would be higher since branched DNA probe assay is not as sensitive as RT-PCR (19).
In conclusion, we must pay attention to HCV infection in diabetic patients, since a high prevalence of HCV infection is observed and it may have an adverse effect on the progression of diabetic nephropathy. However, the accurate reason for the rapid progression of HCV-positive II-DGS remains uncertain. Our study lacked the investigation of HCV RNA on renal biopsy tissue, because the examination of HCV was simply a screening test for renal biopsy. Additional studies are warranted to explain the rapid progression of II-DGS with HCV infection for an effective treatment for diabetic nephropathy and to clarify a possible etiopathologenic role of HCV in diabetes itself. Finally, we must comment that it is uncertain whether the HCV-related rapid decline in renal function is a peculiar phenomenon in II-DGS. It is important to study whether this is also the case in other renal diseases such as MPGN and MN.
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Acknowledgments |
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This work was supported in part by a research grant (Progressive Renal Lesions) from the Intractable Disease Division, Public Health Bureau, Ministry of Health Welfare, Japan, and by a research grant from the Miyagi Prefecture Kidney Association, Japan. The authors thank all the doctors of our associated units for their helpful information about patients, Noriko Tsuchiya and Kiyomi Kisu for their technical assistance, and Drs. Ichiro Tsuji and Atsushi Hohzawa for their kind advice on statistical analyses.
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Footnotes |
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American Society of Nephrology
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References |
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