| Abstract|| |
Hepatitis C virus (HCV) contributed as a risk factor for chronic kidney disease (CKD). Many studies only showed it associated with estimated glomerular filtration rate (eGFR) reduction and albuminuria, but none revealed hematuria data. Besides, liver cirrhosis and viral load as risks for CKD are still yet to be established. This study aimed to assess the prevalence of CKD and its component in hepatitis C and to associate it with liver cirrhosis and viral load. A cross-sectional study using consecutive recruitment on the basis of anti-HCV positivity was done from August 2018 until January 2019. The participants with any renal abnormality on the first meeting were followed prospectively for at least three months. The study was done in Hepatology Clinic Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Liver cirrhosis was defined using transient elastography (>11 kPa). A baseline viral load >100,000 IU/mL was considered as high. CKD was defined as persistence of decreased eGFR and/or albuminuria and/or hematuria for three months. Logistic regression models were used to evaluate adjusted odds ratio (aOR) with adjustment for age, sex, diabetes mellitus, and hypertension. Of the 185 participants, prevalence of CKD was 23.2% [confidence interval (CI) 95% 17.1%–29.3%]. Decreased eGFR was present in 22 (11.9%), albuminuria in 29 (15.7%), and hematuria in 13 (7%). Liver cirrhosis was associated with CKD (aOR 2.948, CI 95%: 1.218–7.136) but not viral load (aOR: 0.93, CI 95%: 0.396–2.185). Renal examination is recommended in all patients with hepatitis C, particularly in patient with liver cirrhosis.
|How to cite this article:|
Widjaja FF, Lydia A, Adithya Lesmana CR, Nugroho P. Chronic kidney disease in Hepatitis C and its association with liver cirrhosis and viral load: Revealing the importance of hematuria. Saudi J Kidney Dis Transpl 2021;32:1310-8
|How to cite this URL:|
Widjaja FF, Lydia A, Adithya Lesmana CR, Nugroho P. Chronic kidney disease in Hepatitis C and its association with liver cirrhosis and viral load: Revealing the importance of hematuria. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 25];32:1310-8. Available from: https://www.sjkdt.org/text.asp?2021/32/5/1310/344750
| Introduction|| |
Globally, approximately 71 million people (1% of total population worldwide) are infected with hepatitis C virus (HCV) with 1.75 million new infection cases per year. This burden is not only related to liver damage but also renal involvement through direct virus attack, immune complexes, complication from liver manifestation and drugs related to the treatment. Hence, Kidney Disease Improving Global Outcomes (KDIGO) have recommended people infected with HCV to be routinely checked for estimated glomerular filtration rate (eGFR), proteinuria, and hematuria at least yearly. Early detection may result in better outcome and delay progression to end-stage renal disease.
It is important to identify not only decreased eGFR and albuminuria but also hematuria since all the three components contributed as criteria of acute glomerulonephritis. Unfortunately, no hematuria data was found. Moreover, the prevalence of decreased eGFR and albuminuria among patients with HCV showed heterogeneity between studies.,, It may be caused by disparity of examination methods and also various prevalence of established risk factors for CKD, such as hypertension (HTN), diabetes mellitus (DM), age,,, and sex in each study.
Other liver factors such as viral load and liver cirrhosis may also contribute in this variation, but the evidence is still limited., Moreover, prior study compared high viral load with non-hepatitis C infected subjects instead of low viral load, and hence it could inappropriately estimate the risk of high viral load. Some previous studies retrieved cirrhosis diagnosis using medical record rather than direct examinations and might oversight early cirrhosis. Hence, this study aimed to know the prevalence of CKD and its component in people with HCV and to explore the association between viral load and liver cirrhosis with CKD.
| Materials and Methods|| |
This study was approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia No: 0711/UN2.F1/ETIK/ 2018. Informed consents had been acquired before any examination was done.
A cross-sectional study followed with a cohort study was done in Hepatology Clinic Cipto Mangunkusumo Hospital, Jakarta, Indonesia. From August 2018 until January 2019, a total of 272 adults patients were selected consecutively based on anti-HCV positivity. After excluding 18 patients with history of hemodialysis, nine patients with positive hepatitis B surface antigen, three patients with human immunodeficiency virus infection (HIV), one patient with renal stones, and 56 patients refused to participate the study, 185 participants were recruited in this study. Among them, participants who had any abnormal kidney damage marker (decreased eGFR and/or albuminuria and/or hematuria) were followed to confirm the persistence of the abnormalities.
All participants were interviewed to acquire information about age, sex, DM, HTN, current HTN medication, status of hepatitis C treatment, time from hepatitis C diagnosis, and encephalopathy. Ascites was assessed by physical examination or ultrasonography. Hepatitis C genotype was also collected when available. Transient elastography (Fibroscan®) was used to define cirrhosis (F4) if the score was greater than and equal to 11 kPa. All patients had fasted at least 6 h before the transient elastography was done. The average value of the transient elastography was taken from 10 times validated measurements and the interquartile range must be <30%. We recorded the result that was examined in the period within six months before or after from the first visit. Ultrasonography was used as alternative if the patient had ascites. Transient elastography and ultrasonography were performed under supervision of gastroenterohepatologist. Serum bilirubin, international normalized ratio, and serum albumin were examined if the subjects had liver cirrhosis to calculate Child Turcotte Pugh (CTP) and natrium-model for end-stage liver disease (Na-MELD) score. Baseline viral load (HCV RNA) was obtained before the participants had any hepatitis C treatment. A viral load serum of >100,000 IU/mL was categorized as high. Serum creatinine to calculate eGFR using CKD-EPI formula, urinalysis to examine erythrocyte cast, and urine analysis to examine urinary albumin to creatinine ratio (ACR) were also examined on the first meeting.
Participants who had decreased eGFR (<60 mL/min/1.73 m2) and/or albuminuria (urinary ACR ≥30 mg/g) and/or hematuria (erythrocyte cast >2 cells/high power field) on the first examination were followed at least three months to confirm the persistency. Participants were defined to have CKD if there were persistency of kidney damage markers such as decreased eGFR and/or albuminuria and/or hematuria for more than three months. The highest eGFR and the lowest urinary ACR among two examinations were considered to be the final results. The final eGFR and urinary ACR were grouped based on KDIGO criteria.
All data analyses were done using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). Categorical variables were presented as frequency and percentage. Numerical variables were shown with mean and standard deviation when it was distributed normally and median and minimum to maximum were used when it was not. The Chi-square test and Fisher test as alternative were used for comparing categorical variables; and Mann-Whitney test as alternative were used for comparing numerical variables between groups with and without CKD. Logistic regression models were used to determine the adjusted odds ratio (aOR) of viral load and liver cirrhosis for CKD by doing adjustment for age, sex, DM, and HTN. Graphical data were built using Microsoft Excel 2016 (Microsoft Corporation, Redmond, Washington, USA) and GraphPad Prism 8 (GraphPad Software, San Diego, California, USA).
| Results|| |
The sociodemographic characteristics and comorbidities of the CKD and non-CKD groups are shown in [Table 1]. Both groups had similar percentages of gender and status of hepatitis C medication. The CKD group was more likely to be older and have HTN, DM, HTN and DM, ascites, and encephalopathy.
|Table 1: Characteristics of the participants with HCV in CKD and non-CKD groups.|
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Of 185 subjects who were recruited, 65 subjects had at least one kidney damage marker (eGFR or albuminuria or hematuria) and were followed and underwent reexamination only on the abnormal result. None of them underwent hemodialysis and was excluded during the follow-up period. [Figure 1] shows the changes in eGFR and urinary ACR of each subject who had abnormality on the first examination. Hematuria was found abnormal in 26 subjects on the first examination and 13 subjects had persisted abnormality on the follow-up period. There were 43 subjects who had persistent abnormalities of one or more kidney damage markers and confirmed to have CKD. Thus, the prevalence of CKD in people infected with HCV was 23.2% [confidence interval (CI) 95% 17.1%–29.3%]. If hematuria was excluded from the diagnostic criteria, the prevalence of CKD was decreased to 21.6%. We further evaluated each kidney damage marker. The prevalence of decreased eGFR was 11.9% (CI 95% 7.2%–16.6%), albuminuria was 15.7% (CI 95% 10.5%–20.9%), and hematuria was 7% (CI 95% 3.3%–10.7%). [Table 2] shows each kidney damage marker in CKD group based on the severity. Majority of the subjects had CKD stage G3a (eGFR45–59 mL/min/1.73 m2) and microalbuminuria (urinary ACR 30–300 mg/g).
|Figure 1: The first and second eGFR and urinary ACR examinations of each subject. The examinations had at least 3 months apart. There were 27 subjects that had eGFR<60 mL/min/1.73 m2 on the first examination and re-examined (a). Among those, 5 subjects had eGFR ≥60 mL/min/1.73 m2 on the second examination. There were 38 subjects that had urinary ACR ≥30 mg/g and re-examined (b); the picture on the right shows the zoom picture of ACR 0–300 mg/g (c). From those, 9 subjects had urinary ACR <30 mg/g on the second examination.|
eGFR: Estimated glomerular filtration rate; ACR: albumin to creatinine ratio.
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Of all participants, high viral load was found in 69.7% participants and liver cirrhosis in 59.5%. Distribution of viral load and severity of liver cirrhosis using CTP and Na-MELD among CKD and non-CKD groups are shown in [Table 3]. [Table 4] shows the association of CKD with liver cirrhosis, viral load, DM, HTN, age, and gender. By doing an adjustment in the analysis, only liver cirrhosis was significantly associated with the presence CKD but not with high viral load [Table 4]. Subjects with liver cirrhosis CTP B and C had higher risk for CKD (aOR: 5.329, CI 95%: 1.741–16.313, P = 0.003) than cirrhosis CTP A (aOR: 2.188, CI 95%: 0.839–5.708) compared to non-cirrhotic subjects. Furthermore, there was no association between CKD and viral load using different cut-offs from 100,000 till 1,000,000 IU/mL [Figure 2]. Among 33 subjects with available genotyping, 25 subjects had HCV genotype 1, four subjects had genotype 2, two subjects had genotype 3, and two subjects had genotype 4.
|Figure 2: Proportion of CKD using different cut-offs in high and low viral load group.|
n=181; 4 subjects' viral load data were missing. Chi-square test was used to associate viral load with CKD. CKD: Chronic kidney disease.
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| Discussion|| |
The prevalence of CKD in this study was relatively high. To the best of our knowledge, this study was the first to include hematuria in CKD assessment among hepatitis C patients. Moreover, some previous studies only used International Classification of Diseases (ICD) code from medical records in diagnosing CKD.
This study also used urinary ACR as recommended by KDIGO in evaluating albuminuria. The population was also limited to subjects infected with HCV since hepatitis B or HIV infection may also cause nephropathy. Re-examination was done in all abnormalities of kidney damage markers to ensure the persistency.
The prevalence of CKD among patients with hepatitis C in this study was higher compared to previous studies ranging 9.2% to 16.5%.,,,, Some reasons may contribute in this discrepancy. Liver cirrhosis proportion was also higher in this study (59.5%) compared to the study in Taiwan (12.9%, based on medical records) and United States (23.7%, based on fibrosis-4 index ≥3.25). The possible reasons for these differences may be attributed to no uniformity in diagnosing cirrhosis and the place of our study that is a tertiary care hospital. Moreover, transient elastography may be more accurate in diagnosing liver cirrhosis compared to medical records and fibrosis-4 index. The recruitment of our study was hospital-based study; meanwhile other studies were population-based studies.
Despite of the higher prevalence of CKD in our study, the prevalence of decreased eGFR was quite similar. In our study, the prevalence of eGFR <60 mL/min/1.73 m2 (11.9%) and eGFR <30 mL/min/1.73 m2 (0.5%) were still in the range of prevalence (2.2 to 30% and 0.2 to 2%, respectively) reported in a meta-analysis of 23 cross-sectional studies in the United States and Taiwan. Moorman et al also found 2% of subjects having eGFR<30 mL/min/1.73 m2 in hepatitis C. Moreover, prevalence of albuminuria (15.7%) was also similar to the prevalence reported in the previous meta-analysis (6.4–27.2%). Hepatitis C may cause proteinuria by direct virus attack or being mediated with insulin resistance that would increase renal cell proliferation and resulted in vasoconstriction. This possible mechanism might be seen in line with high proportion of DM in this study.
No study was found assessing hematuria as the component of CKD. Thus, we did not know the burden of this kidney damage marker. Hematuria was found 7% in our study. This is a big number when compared to glomerulonephritis prevalence (0.69%) in hepatitis C subjects. Although it is not appropriate to compare it directly, since membrano-proliferative glomerulonephritis in hepatitis C may appear as isolated hematuria in 30% patients, nephrotic syndrome in 20%, and nephritic syndrome in 15%.
Another study in the United States found cryoglobulinemia (0.9%), vasculitis (0.2%), and nephrotic syndrome (0.3%) in hepatitis C. In our study, the proportion of albuminuria >3500 mg/g which is related with nephrotic syndrome was found in 2%. It is a high number. Moreover, most of these subjects had direct anti-viral agent (DAA) treatment for hepatitis C which are potential to reduce proteinuria. It is important to prevent the progression of CKD since the cost to treat hepatitis C with symptomatic cryoglobulinemia or vasculitis was 80 times lower compared to hepatitis C with end-stage renal disease.
Liver cirrhosis was found to be a risk factor for CKD in hepatitis C patients (aOR 2.948, CI 95%: 1.218–7.136). A study in Taiwan also showed cirrhotic and hepatitis C patients had adjusted hazard ratio of 3.31 for CKD compared to hepatitis C alone. Our study also found the greater the severity of cirrhosis was, the higher the risk for CKD was. Advanced cirrhosis (CTP B and C) had greater risk for CKD than early cirrhosis (CTP A).
Our study did not reveal any association between viral load and CKD. A study in Taiwan showed viral load >107,000 IU/mL contributed to higher risk for proteinuria and low eGFR. This discrepancy may be caused by some reasons. They compared high viral load group with nonhepatitis C group (anti-HCV negative) and nonchronic hepatitis C (anti-HCV positive and HCV RNA negative), meanwhile we compared it with low viral load group excluding nonhepatitis C group. Thus, this may be concluded that the hepatitis C itself but not the high viral load which possesses greater risk. Moreover, the study in Taiwan used data in 1991 to 1992 and followed 16 months before DAA era, so it was not influenced by DAA treatment. Moreover, they excluded preexisting cirrhosis and used dipstick with cutoff of >15 mg/dL to determine proteinuria. A study in United States with higher cutoff of ≥700,000 copies/mL also showed viral load as a risk for CKD, but it did not exclude HIV coinfection. We applied using different cutoff for viral load, but no association was found [Figure 1].
Another study by Lazo et al showed proportion of decreased eGFR was significantly higher in chronic hepatitis C (anti-HCV and HCV RNA positive) than in previous hepatitis C infection group (anti-HCV positive but HCV RNA negative) (5.2% vs. 2.1%). In contrast, decreased eGFR was higher in nonhepatitis C (anti-HCV negative) (6.8%). Hence, this association is also questionable. There was also no significant difference of albuminuria among three groups.
Based on those results, we hypothesize that viral load serum does not associate with CKD. One of the mechanisms of CKD in hepatitis C is direct viral effect, meanwhile HCV RNA serum did not correspond with virus in the kidney. A study by Cao et al analyzed 21 patients with glomerulonephritis with anti-HCV positive. They found seven patients had HCV RNA serum positive and only six patients had HCV antigen positive in the glomerulus using immunochemistry staining. Moreover, there were only four patients with HCV RNA serum positive out of six patients with HCV antigen positive in the glomerulus.
The limitation of this study is the subjects’ recruitment was done consecutively in Hepatology clinic so that the proportion of cirrhosis is higher and may result in higher prevalence of CKD. It should be used cautiously to extrapolate this data to the community. We also did not explore the etiology of hematuria in this study. Other traditional risk factors for CKD are not excluded in this study since DM and HTN may mediate the progression of CKD in hepatitis C patients. Next, liver cirrhosis might also be overestimated because DAA may reverse liver cirrhosis in 10%–25% patients having sustained virological response. In this study, timing of liver assessment was not done simultaneously with renal examination, so the subjects might have reversibility of liver cirrhosis after DAA treatment. History of medication could not be analyzed because many patients did not check their kidney condition simultaneously when the history taking was done, otherwise they might check it in the next month. Moreover, most of the patients rechecked urine or blood tests after finishing DAA treatment which might also affect their kidney condition.
| Acknowledgment|| |
The authors would like to thank Diar Riyanti, Muhammad Arief Luthfi Parama, and Nurul Fajri Widyasari in helping the recruitment of the participants
Conflict of interest: None declared.
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Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia/ Cipto Mangunkusumo Hospital, Jakarta
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]