Globally, over 71 million people are infected with hepatitis C virus (HCV), resulting in over 399,000 deaths, primarily due to cirrhosis or hepatocellular cancer (HCC)^1,2. As research mostly focuses on liver-associated consequences, especially cirrhosis and HCC, HCV-related mortality and morbidity are typically underestimated. Several patients with HCV have a broad spectrum of extrahepatic symptoms^3,4. Included among these are mixed cryoglobulinemia/cryoglobulinemia vasculitis, B-cell non-Hodgkin's lymphoma, type 2 diabetes mellitus, glomerulonephritis, renal insufficiency, lichen planus, porphyria cutanea tarda, and cardiovascular disease events⁵.

Since its discovery, HCV has been related to chronic kidney disease (CKD). A viral infection may be a cause or an effect of CKD⁶. HCV infection is related to a higher incidence of diabetes mellitus and CKD and a higher risk of systemic (particularly cardiovascular) consequences. The basic symptom of HCV-induced glomerulonephritis has been widely char- acterized; however, the virus has been associated with CKD in various other ways. Growing data indicate the link between HCV infection and initial CKD, as well as the rapid progression of CKD to end-stage renal disease (ESRD) requiring transplant or hemodialysis^6-10.

Fortunately, evidence suggests that >95% of patients with late-stage CKD and recipients of kidney transplantation can attain sustained virologic response. All patients with CKD and HCV infection should be considered for therapy with direct-acting antivirals (DAAs), prioritizing those with symptomatic cryoglobulinaemic vasculitis, severe liver fibrosis, and CKD stages 4~5, according to international guidelines. DAA therapy can be deferred until after transplantation for recipients whose transplant waiting time is drastically reduced by accepting an HCV-positive organ. The long-term renal safety of DAAs is a new concern that deserves reevaluation^7,11,12.

This study aimed to determine the association between HCV infection and chronic renal diseases.

Protocol

This study was conducted in a manner that is compliant with the requirements outlined in the Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 guide- lines to ensure that the study findings are honest and accurate.

Criteria for eligibility

This literature review aimed to investigate and analyze the findings of previous studies about the connection between HCV infection and chronic renal disorders. Ongoing investi- gations have uncovered a serious obstacle to be addressed. Participation in the study requires meeting one or more of the following criteria: (1) For papers to be considered for publication, they must be written in English and discuss the association between HCV infection and CKDs. (2) The analysis takes into account articles that were published after 2018 but before the study period. Some examples include editorials, submissions without a DOI, published review articles, and duplicate journal entries.

Search strategy

The terms "hepatitis C" and "chronic kidney disease" were used. The search for studies eligible for inclusion in the systematic review was conducted from February 15, 2023, using the PubMed and SagePub databases by inputting the following keywords: ("hepatitis c, chronic" [MeSH Terms] OR "chronic hepatitis c" [All Fields] OR "hepatitis c chronic" [All Fields]) AND ("kidney diseases" [MeSH Terms] OR ("kidney" [All Fields] AND "diseases" [All Fields]) OR "kidney diseases" [All Fields] OR ("renal" [All Fields] AND "disease" [All Fields]) OR "renal disease" [All Fields]).

Data retrieval

After reviewing the titles and abstracts of other studies, the author decided to alter the criteria for inclusion. Additional resources for the research include specifics regarding the newly developed criteria. This highlighted how significant and intricate the issue is, indicating the need for additional research into the matter. Examining numerous studies that were all organized in the same way led to the discovery of this conclusion. In systematic reviews, eligible papers are limited to only those that satisfy all the inclusion criteria. This made it much simpler to zero in on significant specific items.

Our research team did not accept the study suggestions because they did not satisfy our established standards. As a result, the investigation certainly would be finished. During the investigation, names, authors, publication dates, locations, study activities, and parameters were collected. The following is a list of the various categories of products that can be purchased. If you practice using these talents, you will be able to improve at using them. The source of this information will possibly influence how it's portrayed here.

Quality assessment and data synthesis

Each author independently reviewed the studies based on their titles and abstracts before deciding which articles to analyze. Then, all papers that have the potential for inclusion in a systematic review were assessed. The articles that will be evaluated will be chosen based on our judgment, which was the basis for our selection of studies to review (Fig. 1). This makes the assessment of various articles simpler. Which previous studies can be incorporated into the review, and how can this be done?

Figure 1. Article search flowchart

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Studies showed that persistent HCV infection was signifi- cantly associated with CKD [odds ratio (OR) 1.33; 95% confidence interval (CI) 1.06~1.66; p = 0.013], whereas no significant link was found between CKD and spontaneous HCV clearance (OR 1.23; 95% CI 0.79~1.90; p = 0.364), HBV infection (OR 0.73; 95% CI 0.44~1.19; p = 0.201), or HBV/HCV co-infection (OR 1.40; 95% CI 0.81~2.40; p = 0.234). After anti-HCV therapy, the serum creatinine concen- tration was significantly decreased (76.0, 75.5~79.4 μmol/L) from the pretreatment level (95.0, 93.0~97.2 μmol/L), both in patients who showed an end-of-treatment virological response (ETVR) and those who did not (p < 0.001). In both the ETVR and non-ETVR groups, the proportion of patients with an estimated glomerular filtration rate (eGFR) of ≥90 mL /min/1.73 m2 increased significantly (p < 0.001), whereas the proportion of those with an eGFR of <60 mL/min/1.73 m2 decreased significantly (p < 0.001)¹³.

Hsu et al.^₁₄ detected HCV in 111 of 233 (47.6%) patients with CKD and 167 of 946 (17.7%) patients without CKD. CKD occurs in 226.9 per 1000 person-years of patients with HCV infection and 14.8 per 1000 person-years in those without HCV infection. For incident CKD, the adjusted relative risk of HCV infection was 7.9 (95% CI 5.0~12.0). Patients with HCV infection and normal renal function had an in- creased risk of eGFR reduction at 1, 2, and 3 years. The risk associations remained significant in models that included a 50% decline in eGFR at 3 years and additional subgroup analyses. The higher risks of eGFR reduction were also well-known among all patients with both HCV infection and CKD.

In a multivariate time-varying Cox regression model con- ducted by Park¹⁵, patients with HCV infection exhibited a 27% greater risk of CKD than those without HCV infection (hazard ratio [HR] 1.27; 95% CI 1.18~1.35). Those who had the least effective HCV treatment for dual, triple, or all-oral therapy had a 30% decreased risk of CKD development (HR 0.70; 95% CI 0.55~0.88). In addition, compared with the non-HCV group, the HCV group had a twofold and nearly 17-fold greater risk of membranoproliferative glomerulonephritis (MPGN) (HR 2.23; 95% CI 1.84~2.71) and cryoglobulinemia (HR 16.91; 95% CI 12.00~23.81), respectively.

Liu et al.¹⁷ showed patients receiving sofosbuvir (SOF)-based direct-acting antiviral (DAA) treatment experienced a significant on-treatment decline in eGFR (adjusted slope coefficient difference: -1.24 mL/min/1.73 m2/month; 95% CI -1.35 to -1.13; p < 0.001) and a significant off-treatment improvement (adjusted slope coefficient difference: 0.14 mL /min/1.73 m2/month; 95% CI 0.08~0.21; p = 0.004) com- pared with patients receiving SOF-free DAAs. Multivariate analysis showed age per 1-year increase (adjusted slope coefficient difference: -0.05 mL/min/1.73 m2/month; 95% CI -0.05 to -0.04; p < 0.001), SOF-based DAAs (adjusted slope coefficient difference: -0.33 mL/min/1.73 m2/month; 95% CI -0.49 to -0.17; p < 0.001), and CKD stage (adjusted slope coefficient difference: -1.44 mL/min/1.73 m2/month; 95% CI -1.58 to -1.30; p < 0.001 for stage 3 vs. 1, and -3.59 mL/min/1.73 m2/month; 95% CI -3.88 to -3.30; p < 0.001 for stage 2 vs. 1) were independent factors that affect eGFR evolution from baseline to off-treatment week 24.

Chen et al.¹⁵ showed that the CKD risk was considerably lower in the treated cohort than in the untreated group (7-year cumulative incidence, 2.6%; 95% CI 0.7~6.9%; p = 0.001), with an adjusted HR of 0.42 (95% CI 0.20~0.92; p = 0.03). The findings also remained true for the HCV group. At 7 years, 58 patients were treated to prevent one case of CKD. The risk reduction for CKD was the largest (0.35; 0.14~0.87; p = 0.024) among patients with HCV infection who received IFN-based therapy (IBT) for at least 6 months. Multivariable stratified analysis confirmed that individuals with HCV infection having hyperlipidemia, diabetes, and hyper- tension and those without coronary heart disease had a lower risk of CKD¹⁶.

Both chronic renal disease and HCV infection are serious public health problems worldwide. HCV infection is linked to various extrahepatic symptoms that can occur in various organs, including the kidneys. It has recently come to light that a significant connection was found between HCV and chronic renal diseases. Hemodialysis is sadly a risk for HCV infection when it is used to assist patients who have reached the terminal stage of renal failure^20,21.

Despite significant treatment advancements, the frequency of HCV infection among patients receiving hemodialysis is still significantly greater than that of the general population. Patients on hemodialysis and recipients of kidney transplan- tation have a decreased chance of surviving if they have HCV infection^20,21.

A study showed the incidence of CKD related to HCV infection was greater (217.3 per 1000 person-years) than prior estimates. Differences in CKD classification, HCV prevalence, and viral genotyping variation may explain the disparities found among studies¹⁴. The increased risks of incident CKD and eGFR decrease associated with HCV infection, as iden- tified in our analysis, were consistent with reports of some previous studies but inconsistent with others^14,15.

Some cross-sectional studies used eGFR cut-values from the Modification of Diet in Renal Disease or the CKD-EPI equation to define CKD, whereas other prospective studies used male-predominant participants or disease code-based registry claims data to determine renal outcomes rather than changes in serum creatinine or eGFR slopes. As a result, repeated measures of blood creatinine and urine protein decreased, potentially underestimating the true prevalence of CKD²².

In individuals who have HCV infection, ESRD can have different causes. HCV infection can set off a chain reaction of immunological responses, which can then lead to kidney attacks and development of glomerulonephritis. In addition, HCV is linked to insulin resistance and dyslipidemia, all of which indirectly increase the risk of renal disease development²³.

Glomerulonephritis can develop in several years, if not decades, following an HCV infection. The mechanism for HCV-induced MPGN is thought to be immune-complex mediated (formation of antigen-antibody immune complexes from chronic infection), and these immune complexes activate the classical complement pathway, causing deposition of immunoglobulins, complement factors, and both kappa and lambda light chains in the mesangium and capillary walls. HCV-NS3 viral antigen deposits were found in kidney tissues of individuals with HCV RNA positivity and MPGN^15,24.

Cryoglobulins are immunoglobulins (Ig) that become in- soluble at temperatures below the body temperature and rehydrate when rewarmed. These cryoglobulins are immun- ological complexes generated by monoclonal Ig M (typically IgM rheumatoid factor), polyclonal IgG, and HCV RNA that are deposited in small- and medium-sized capillaries of the skin, kidneys, and peripheral nerves in people with HCV in- fection^15,24.

Glomerulonephritis is caused by the accumulation of these immune complexes in the renal mesangium. Although proteinuria below the nephrotic range, microscopic hematuria, mild-to-moderate renal insufficiency, and arterial hypertension are typical clinical signs, 30% of patients with chronic HCV and cryoglobulinemia report nonspecific symptoms such as purpura, asthenia, and arthralgia. Vasculitis involving the kidney, skin, and nerves affects <10% of the population^15,24.

Nephritic disease, nephrotic syndrome, or isolated protein- uria can be the clinical manifestation of HCV-related kidney disorders. These diseases can occur with or without a reduction in renal function. MPGN, membranous glomerulopathy, IgA nephropathy, focal segmental glomerulosclerosis, mesangial proliferative glomerular nephritis, or tubulointerstitial nephritis are pathological abnormalities that can be seen on a renal biopsy²⁵.

The treatment of HCV in patients with ESRD with conven- tional or pegylated interferon (IFN) with or without ribavirin (RBV) continues to be a clinical challenge because of a low response rate, a high dropout rate due to poor tolerability, and a large number of unmet requirements. In patients with mild-to-moderate renal impairment and HCV infection, the introduction of novel DAA medicines for HCV treatment might bring about a significant shift in the treatment strategy. However, whether the most recent treatments for HCV are risk-free for those who have severe renal impairment has not yet been shown^20,26.

This nationwide cohort study found that patients with HCV infection who received IBT for ≥6 months and those with hyperlipidemia, diabetes, hypertension, and without coronary heart disease, had a lower chance of developing CKD than those with HCV infection who did not get IBT. These results show that HCV infection may play a pathogenic role in CKD development and may provide therapeutic guidance to explain the long-term usage and renal benefits of IBT in patients with HCV infection16.

Antiviral therapy with IFN with RBV can enhance renal function and reverse CKD in individuals with HCV infection. Persistent HCV infection was independently linked with CKD13,18. Early therapy benefits patients with cirrhosis who are not candidates for kidney transplantation. The best time to treat patients with cirrhosis, including those with subclinical portal hypertension, who are kidney transplantation candi- dates will be determined by the policies of specific transplant facilities. HCV treatment standards must be revised regularly to reflect improvements. Hepatology and transplant nephrology must collaborate continuously to adjust transplant policy to this patient population²⁷.

Because IFN is mostly broken down in the kidneys, IFN treatment in individuals with renal disease may result in con- siderable IFN buildup. PegIFN was developed, which attaches polyethylene glycol to the IFN molecule, making it more stable and having a longer half-life in the plasma. PegIFN requires only a weekly injection rather than thrice weekly injections of IFN. The two formulations of pegylated IFN are PegIFN-α2a and PegIFN-α2b²⁸.

The latter is weight based at 1.5 mcg/kg, whereas the dose of PegIFN-α2a is 180 mcg regardless of the body weight. PegIFN-α2a is metabolized in both the kidneys and liver, whereas PegIFN-α2b is only in the kidneys. The plasma con- centration of PegIFN is significantly elevated in patients on hemodialysis; thus, PegIFN dose must be reduced. For patients with creatinine clearance of <30 mL/min and on hemodialysis, the PegIFN-α2a dose should be reduced from 180 mcg to 135 mcg weekly²⁸.

Urgent therapy with either elbasvir/grazoprevir or ombitasvir /dasabuvir/paritaprevir/ritonavir for G1 and G4 (without DSV) or G/P for G1-G6 should be considered for a kidney transplantation candidate with subclinical portal hypertension who may be accepted as a kidney transplantation candidate alone rather than a combined liver/kidney candidate with viral clearance and where extrahepatic manifestations of HCV, i.e., cryoglobulinemia, dictate urgency. It is an exciting period for HCV antiviral therapy and we are now seeing patients with concomitant ESRD benefit²⁷.

Other studies have shown the efficacy of sofosbuvir therapy. Little doubts remain on whether sofosbuvir is effective in treating HCV; nevertheless, findings of the drug's potential nephrotoxicity are up for debate. That is, the use of sofosbuvir led to a decline in kidney function during therapy but resulted in an improvement after stopping treatment. Before beginning DAA therapy in patients with HCV infection, our study leads us to believe that treating doctors should be aware of the risk factors for renal impairment as a precautionary measure17.

Patients with HCV infection had a significantly increased probability of acquiring CKD. Individuals with HCV infection who had normal renal function had higher risks of renal disease progression compared with patients with HCV in- fection who had CKD. Anti-hepatitis treatment can cause variations in eGFR, leading to either an improvement or a worsening of the patient's condition.