Hepatorenal Syndrome (HRS) is a disease of acute renal function worsening caused by systemic circulation dysfunction on the basis of severe liver disease. As one of the complications of cirrhosis and , it has a poor prognosis and low survival rate. The survey showed that the incidence of HRS in patients with cirrhosis increased with the prolonged severity and duration, at 18% at 1 year follow-up and 39% at 5 years follow-up. Patients with ascites cirrhosis have acute renal failure with a significant decrease in the rate of glomerular filtration rate , that is, serum creatinine (SCr) > 1.5 mg/dL (133 μmol/L) can be diagnosed as acute renal injury (AKI). Other causes of AKI are excluded, and HRS[2] can be diagnosed as combined with no obvious organic lesions in the kidneys. HRS can be divided into two types according to the severity and progression of renal injury. One represents acute damage to renal function, namely HRS-AKI; the other is chronic renal dysfunction, namely HRS-CKD[3]. Treatment is required as soon as possible after diagnosis. Vasoconstrictors such as vasopressin analogs (onivasopressin and terivasopressin), alpha-adrenergic agonists (norepinephrine and Midojun), and somatostatin analogs (octreotide) combined with albumin , have been proven to be effective. Among them, terivasopressin and albumin are the first-line treatments for [4] in most cases. Studies have shown that terlivasopressin can effectively reverse HRS and improve short-term survival, but its efficacy is limited, and even if effective, the early mortality rate is very high in the absence of liver transplantation. Liver transplantation is the only cure for HRS. But in the long run, the glomerular filtration rate in patients with HRS liver transplantation is still lower than in patients without HRS. In addition to the impact on patient survival and prognosis, the huge medical cost of HRS will cause significant socio-economic burden [5].
Traditional Chinese medicine can assist in the treatment of HRS, and has the characteristics of diverse methods, few side effects and low costs. Based on the clinical manifestations of HRS and the understanding of its etiology and pathogenesis of traditional Chinese medicine, the author believes that the disease belongs to the category of "swelling" and "-link " in traditional Chinese medicine. From the perspective of Yin and Yang and Five Elements, the HRS formed by liver and gallbladder system diseases lead to renal failure is equivalent to the category of "child diseases and mothers" in traditional Chinese medicine theory. In recent years, multiple clinical research results have proved that the combination of traditional Chinese medicine and Western medicine has achieved certain results in the treatment of HRS, and traditional Chinese medicine has provided new ideas and methods for the early treatment of HRS. Therefore, this article reviews the relevant literature on the diagnosis and treatment of HRS in traditional Chinese and Western medicine in recent years, providing a reference for further research on the treatment of HRS in traditional Chinese and Western medicine.
1HRS Diagnosis
1.1 Diagnostic standards and typing of HRS
HRS Diagnosis As years of clinical trial results have been continuously updated and improved, the most commonly used diagnostic standard in the world is the revised consensus recommendation [6] released by the International Ascites Club in 2015, which includes the new definition and classification of modified AKI. The most common type of renal insufficiency in cirrhosis is AKI, and HRS is a special type of AKI. HRS is divided into two categories: HRS-AKI and HRS-NAKI. The past type 1 HRS is now called HRS-AKI. According to the updated definition, the minimum creatinine value is not required for diagnosing HRS-AKI. That is, even if the SCr is less than 2.5 mg/dL, HRS-AKI can be diagnosed. Functional renal injury in patients with cirrhosis who do not meet the HRS-AKI criteria is called HRS-NAKI, defined by the estimated glomerular filtration rate (eGFR) rather than SCr. If eGFR <60>-1·1.73 m-2 and the duration is less than 3 months, it is called HRS acute nephropathy (HRS-AKD), and if the duration is more than 3 months, it is HRS chronic nephropathy (HRS-CKD). For details of specific diagnosis and typing, see Table 1.
The "Guidelines for Diagnosis and Treatment of Ascites and Related Complications of Cirrhosis" issued by the Hepatology Branch of the Chinese Medical Association in [2] is: cirrhosis combined with ascites; no shock ; SCr elevation is greater than 50% above the baseline level, >1.5 mg/dL (133 μmol/L); if diuretics are used for at least 2 days and human albumin is 1 g·kg-1·d-1·d-1 expands the capacity until the maximum is 100 g/d, and there is no continuous improvement in renal function (SCr <>
1.2 The urine biomarker of HRS
According to current diagnostic criteria, it is still difficult to distinguish HRS from acute tubular necrosis (ATN). In recent years, biomarker in some urine has been considered to be the key to distinguishing HRS from ATN. Such as neutrophil gelatinase-associated lipoprotein (NGAL), α-1 microglobulin, β-2 microglobulin, retinol binding protein , proinflammatory cytokine IL-18, renal injury molecule-1 (KIM-1; also known as HAVCR1), liver fatty acid binding protein (L-FABP; also known as FABP1) and albumin. Among them, NGAL is the most widely studied biomarker among patients with cirrhosis, showing the greatest accuracy in the differential diagnosis of ATN and AKI-HRS [7]. However, the current study of these biomarkers was conducted without ATN histological confirmation, and the results may be biased. Treatment of
2HRS
2.1 Current status of Western medical treatment of HRS
HRS patients often develop rapidly, so treatment should be started as soon as possible after HRS diagnosis. First of all, supportive measures should be taken, bed rest, and high-calorie, easy-to-digestible diet should be given, blood pressure, urine volume should be closely monitored, and fluid balance should be maintained. Monitor liver and renal function and clinically evaluate the status of concomitant cirrhosis complications. Avoid excessive intake of liquids, prevent liquid overload and the occurrence of diluted hyponatremia [2]. Secondly, it is necessary to prevent bacterial infections, culture blood, urine and ascites in a timely manner, detect infections as soon as possible, and use broad-spectrum antibiotics to treat. Nephrotoxic drugs and diuretics should be avoided, and small-volume therapeutic puncture should be performed if necessary to control ascites. Beta blockers have potential harm to circulation and renal function and should be discontinued during the treatment of spontaneous bacterial peritonitis .
2.1.1 Vascostal agent
The function of the vasoconstrictor is to cause visceral vasoconstriction, leading to an increase in effective circulating blood volume, thereby increasing renal perfusion and glomerular filtration [6]. Several randomized controlled trials of have confirmed the efficacy of vasoconstrictive drugs, which is the main treatment for AKI-HRS [8]. Currently available drugs include terivasopressin, norepinephrine, and a combination of Midojson and octreotide. Terivasopressin is the most commonly used vasopressor. It is a synthetic posterior vasopressin analogue with obvious posterior vasopressin 1A receptor effect and is mainly used as a visceral vasopressin vasopressin. Studies have found that terlivasopressin can stimulate the release of corticotropin and cortisol , which may offset the common relative adrenal insufficiency in patients with decompensated cirrhosis. Patients with systemic inflammatory responses have better effect on reversing AKI-HRS after using terlivasopressin, which may be related to the postdiuretic vasopressin-mediated anti-inflammatory effect of [8-9]. The efficacy range of terivasopressin combined with albumin in achieving complete reversal of HRS is 19% to 56%, while the efficacy range of albumin alone is 3% to 14% [10]. One study, [11], found that the reversal rate of terivasopressin combined with albumin for HRS was 29.1%, while that of 15.8% in the albumin combined with placebo group (P <0.012).> adrenaline . It is an alternative to terivasopressin and is widely used to treat HRS due to its price advantage. Norepinephrine is also safe and effective for HRS-AKI. In some small randomized studies, the HRS reversal rate is similar to that of terivasopressin, with a range of 39% to 70% [12] . Midojun is an adrenaline drug, oral combined with subcutaneous octreotide, which is another alternative. A study of [13] compared the efficacy of midojn/octreotide combined with terlivasopressin and found that the complete response rate of midojn/octreotide was only 4.8%, terlivasopressin was 55.5%, and the total response rate (complete or partial) was 28.6% and 70.4%, respectively.
has Meta analysis [14] summarized 13 randomized controlled trials using vasoconstrictors to treat HRS and found that teripurin is the most effective drug to reverse HRS, and norepinephrine is as effective as teripurin. Both drugs are better than Midojn and octreotide in HRS survival. But these drugs have no benefit to HRS recurrence or patient survival.
According to the current literature [15], these drugs have side effects. Among them, the main side effects of terivasopressin include abdominal cramps and diarrhea in about 20% of patients, and rapid arrhythmia or chest pain in . A small number of patients experience ischemia in the intestine or skin and limbs. The main side effects of norepinephrine are nausea, vomiting, anxiety and arrhythmia . The side effects of Midojun/octreotide are slow arrhythmias, abnormal sensation, abdominal pain, diarrhea, cholelithiasis and hyperglycemia .
2.1.2 Albumin
Albumin infusion is crucial for the effective treatment of AKI-HRS. Albumin can play a role in the treatment of HRS through volume expansion, positive cardiac contraction, antioxidant and immunomodulatory properties. In a single non-random study comparing terli vasopressin combined with albumin and single unique vasopressin [16], terli vasopressin combined with albumin had a more significant efficacy (77% vs 25%, P=0.03). In addition, albumin can also reduce endothelial activation in patients with spontaneous bacterial peritonitis [17]. In vitro albumin dialysis molecular absorption and circulation system is a method to treat refractory acute and chronic liver failure. Although in a randomized study of 166 patients, patients receiving standard treatment had similar survival rates as those receiving in vitro albumin dialysis. However, in vitro albumin dialysis has advantages in improving encephalopathy, lowering bilirubin and improving SCr. Therefore, in vitro albumin dialysis may be another option for HRS patients and liver transplant patients.
2.1.3 Transjugate intrahepatic portal shunt (TIPS)
TIPS aims to reduce portal vein pressure and has significant benefits for patients with cirrhosis who cannot tolerate diuretics, refractory ascites, and difficult to treat varicose bleeding. This surgery has a greater risk, while HRS patients are usually too severe to be generally difficult to accept, so few studies have been conducted on the role of TIPS in AKI-HRS [19]. A small number of studies have shown that after TIPS treatment of AKI-HRS, the renal function of the patients was significantly improved, the levels of plasma renin activity , aldosterone and norepinephrine decreased, SCr, serum sodium and urine volume were significantly improved, and the survival was extended [20-21].
2.1.4 Renal replacement therapy (RRT)
RRT may be suitable for patients with non-responsive to drug treatment and accompanied by volume overload, uremia or electrolyte disorder . RRT cannot improve the survival rate of HRS patients and is mainly used in the transition period of HRS liver transplantation [22]. The use of RRT in patients with non-transplant indications, especially in HRS patients, has been controversial. A recent randomized controlled trial in patients with critically ill liver disease [23] showed that early RRT application has no prolonged effect on survival. Therefore, RRT should be used with clinical basis.
2.1.5 Liver transplantation or concurrent liver and kidney transplantation
HRS is functional renal injury caused by systemic circulation dysfunction caused by severe liver disease, so liver transplantation is expected to eliminate liver dysfunction and portal hypertension, thereby improving renal function. Currently, liver transplantation is still the best treatment for AKI-HRS [24]. However, kidney damage is often related to a variety of factors, such as the duration of kidney damage, and underlying diseases such as diabetes , and 10% of patients with AKI or CKD have persistent or progressive renal failure after receiving liver transplantation alone. Therefore, liver and kidney transplantation is recommended at the same time, but there are problems such as shortage of donors, differences between donor organs and recipients to be transplanted [25].
2.1.6 New drug
According to the current treatment methods of vasoconstrictors and albumin, only 50% of patients respond to treatment, and a new treatment plan is urgently needed. A new selective posterior vasopressin 1A receptor agonist, celepril, was recently studied as an alternative to posterior vasopressin for septic shock , showing a lower risk of hyponatremia , volume overload and pulmonary edema in animal models of sepsis. Its role in HRS still needs further study [26]. A recombinant human relaxin-2, a drug that acts on the renal vascular system, can increase renal blood flow, reduce renal vascular resistance, and reverse endothelial dysfunction.Total renal artery blood flow increased by 65% when treating patients with compensatory cirrhosis. With the study of disease-related molecular patterns, pathogen-related molecular patterns and downstream signaling, it was found that granulocyte colony stimulating factor may increase the number of leukocyte leukocyte in peripheral blood and reduce the infection that may trigger HRS; hexonecocoline was found to be a phosphodiesterase inhibitor with anti-TNFα activity and anti-inflammatory effects, and it is currently considered safe and effective for AKI-HRS patients [27-28].
2.2 Current status of traditional Chinese medicine treatment of HRS
Traditional Chinese medicine believes that HRS is mostly in the late stage of chronic liver disease, and the symptoms in clinical practice are relatively complex, and a single typical syndrome is rare, and often all kinds of symptoms are mixed. The pathogenesis is characterized by the deficiency and the complexity of deficiency and excess. The main locations of the disease are the liver, spleen, and kidneys, involving lungs, bladder, , three burners, and many internal organs are all diseases. Qi, blood, water, phlegm, blood, stasis, and turbid toxins accumulate in the body. When diagnosed, pay attention to the qi in blood, which is deficiency and solid, as well as the severity of phlegm, dampness, blood stasis and toxic evils. Treatment should be to regulate the liver, strengthen the spleen, benefit the kidney, promote the lungs, and promote the three burners; to eliminate phlegm and remove dampness, remove blood stasis and detoxify; or to strengthen the body, or to eliminate evil first, or to treat both the symptoms and the root causes, and to strengthen the body and eliminate evil as the treatment principle.
2.2.1 Syndrome Treatment
Tang Shixia et al. [29] Type I HRS is divided into two syndrome types according to traditional Chinese medicine syndrome treatment, damp heat and blood stasis resistance type and yang mild water generic type. The treatment method for dampness, heat, blood stasis and obstruction is to remove blood stasis, promote gallbladder and regulate blood. The prescription is to add or subtract Xiaoji Yinzi; the treatment method for yang mild water is to replenish Zhenyang, to transport spleen and eliminate dampness. The prescription is to use Zhenwu Decoction combined with Liuwei Dihuang Wan to add or subtract. Type II HRS can be divided into three types according to its clinical symptoms. liver qi stagnation , water and dampness block the symptoms. The treatment method is to relieve liver qi and promote qi and promote diuresis. The prescription is Si Ni San combined with Wuling San plus and subtract; liver and kidney yin deficiency , damp heat syndrome syndrome, the treatment method is to nourish the liver and kidney, clear heat and dampness, the prescription is to use Yiguan Decoction and Yinchenhao Decoction to add and subtract; spleen and kidney yang deficiency , phlegm and stasis syndrome, the treatment method is to warm the kidney and strengthen the spleen, remove blood stasis and eliminate phlegm, promote diuresis and reduce swelling, and the prescription is Fuzi Lizhong Decoction and Gexia Zhuyu Decoction. Zeng Sheng believes that alcohol poisoning, damp heat and epidemic poisoning are the main causes of HRS. The pathogenesis is spleen and kidney deficiency, liver qi stagnation, phlegm, turbidity and blood stasis, which leads to damage to the liver, spleen, and kidney, and imbalance in the body's metabolism and causing the disease. HRS is divided into four types: liver qi stagnation and water and dampness stagnation syndrome. The treatment is to relieve liver qi and promote qi. The prescription is to add and subtract Weiling Decoction; spleen yang deficiency and blood overflow syndrome is to warm yang and strengthen the spleen, nourish blood and stop bleeding. The prescription is to add and subtract Huangtu Decoction; liver and gallbladder dampness and heat, blood stasis and heat syndrome is to treat liver and gallbladder dampness and blood stasis and regulate blood. Gegenqilian Decoction is to add and subtract; spleen and kidney deficiency and phlegm and stasis are to treat spleen and kidney deficiency, promote qi and promote phlegm and eliminate phlegm and remove blood stasis. The prescription is to treat Jisheng Shenqi Wan Hegexia Zhuyu Decoction plus and subtract [30].
There is currently no clinical practice guide for clinical for traditional Chinese medicine treatment of HRS in the world. The "Guidelines for Diagnosis and Treatment of Liver and Kidney Syndrome" compiled by this research group combined with previous literature collation and expert discussion opinions to sort out the diagnosis and treatment of HRS, and clarified the HRS Chinese medicine diagnosis , differential diagnosis and syndrome differential treatment standards.HRS is divided into 7 different syndromes: liver depression, qi stagnation, water and dampness internal obstruction, the treatment method is to relieve liver depression, strengthen the spleen and relieve dampness, the recommended prescription Chaihu Shugan San ("Medical General") Heweiling Decoction (" Miraculous Prescription ") Add or subtract; spleen and kidney yang deficiency and water and dampness are deficient, the treatment method is to strengthen the spleen and warm the kidney, transform qi and promote water, the recommended prescription Zhenwu Decoction (" Typhoid Treatise on Febrile Diseases ") Add or subtract; liver and kidney yin deficiency and water and dampness are decomposed, the treatment method is to nourish the liver and kidney, clear heat and remove dampness, the recommended prescription Yiguan Decoction ("Continued Famous Doctors") He Yinchenhao Decoction ("Treatise on Febrile Diseases") or Zuogui Wan ("Jingyue Quanshu") Add or subtract; turbid toxin congestion and stomach qi upside down syndrome, the treatment method is to detoxify and reduce turbidity, harmonize the stomach and reduce reversal, and the recommended prescription is to detoxify and reduce turbidity, and promote The recommended prescription is Huanglian Wendan Decoction ("Liuyintiaobian") combined with Dahuang Huanglian Xiexin Decoction ("Treatise on Febrile Diseases"); the liver and gallbladder dampness, heat, toxins and blood stasis are combined with the treatment method to clear the liver and promote blood circulation. The recommended prescription is Longdan Xiegan Decoction ("Medicine General") is added and subtracted; the evil toxins are invasive and blood heat, and the wind is moving. The recommended prescription is to cool down serum, heat, and stop wind and stop spasms. The recommended prescription is Xijiao Dihuang Decoction (" Waitai Secret ") combined with the Lingyang Goutong Decoction ("Re-revised Popular Treatise on Febrile Diseases") is to add and subtract; the internal accumulation of dampness, qi stagnation and blood stasis are to promote qi and promote blood circulation, and to remove dampness and detoxification. The recommended prescription is Luqi San and Huanglian Jiedu Decoction ("Waitai Secret 日本") and Jiyingyin ("Haitai Secret 日本") is to add and subtract [31].
2.2.2 Clinical trial
In recent years, the combination of traditional Chinese medicine and traditional Chinese and Western medicine has achieved significant results in the treatment of HRS. Zhu Bingbing [32] retrospectively collected 190 hospitalized patients with decompensated cirrhosis and HRS in Ditan Hospital. According to whether Chinese medicine treatment was used after diagnosis, it was divided into 118 non-Chinese medicine cohorts and 72 Chinese medicine cohorts. Among them, if blood stasis blocks the meridians and liver and kidney deficiency, take Fuzheng Huayu Capsule ; if blood stasis blocks the meridians, qi and blood deficiency, and heat and toxins, , take compound brilliance, soft liver tablets ; if liver and spleen deficiency and blood stasis and heat syndrome are stagnant, take Anluo Huaxian Pill; if liver depression and spleen deficiency, , qi stagnation and blood stasis, take Jiuwei Gantai Capsule . The results showed that the mortality rate of patients using anti-fibrotic Chinese medicine was lower within 2 years, and the survival time was longer than that of the group without Chinese medicine. The use of anti-fibrotic Chinese medicine may be related to the reduction in mortality rate and the prolonged survival time in patients with decompensated cirrhosis and HRS. According to literature, Wang Jianyan and other [33] found that the treatment of liver and kidney yin deficiency HRS with octreotide combined with Yiguan Dan and Zhuling Decoction can effectively improve symptoms, accelerate the reduction of limb edema and abdominal bloating, and is safe and reliable. Yao Yao et al. [34] believes that the addition of self-prepared Wenyang Xiaoyin Decoction is beneficial to improve the liver and kidney function of patients with spleen and kidney yang deficiency syndrome and HRS, so that the patient's portal vein inner diameter is reduced and blood flow is reduced. The mechanism is related to regulating the levels of TNFα, NO, and sICAM-1 in the serum to reduce local inflammatory damage, improve blood flow in the liver, reduce portal vein vascular resistance, and exert hepatogenic protection. Qu Zhiwei et al. [35] found that kidney-tonifying and strengthening the spleen method significantly improved liver and renal function in HRS patients. Cao Yujuan et al. [36] found that HRS patients with cirrhosis No. 1 Decoction plus or subtraction combined with ascites ultrafiltration and reflux can effectively improve liver and kidney function, control the status of the micro-inflammatory group, and have a significant prognosis effect.
2.2.3 Basic research
There are few basic research on traditional Chinese medicine treatment of HRS. Yi Guodong et al. [37] explored the mechanism of the protective effect of Schisandra et al. , an active substance derived from the Chinese herbal schisandra et al. 4, on HRS rats. It was found that Schisandra et al. can improve the liver and kidney function of HRS rats, and its mechanism of action may be related to schisandra et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al.
2.2.4 Other treatment methods
未分类彩 et al. [38] was added with traditional Chinese medicine retained enema for treatment of HRS on the basis of routine treatment of Western medicine. The research results show that the clinical efficacy of adding traditional Chinese medicine retained enema for treatment of HRS on the basis of routine treatment of Western medicine is significantly better than that of routine treatment of Western medicine alone, which can significantly improve patient symptoms, improve liver and renal function, delay renal failure, and prevent complications. Li Shuangquan [39] observed the effect of traditional Chinese medicine combined with acupuncture to treat HRS. The results showed that based on the routine treatment of Western medicine, combined with traditional Chinese medicine, acupuncture Shenshu , Qihai, and Zusanli , can significantly alleviate the disease, improve survival rate, and improve prognosis.Deng Changqing et al. observed the clinical efficacy of external Chinese medicine for treating cirrhosis and HRS. They found that on the basis of symptomatic comprehensive treatment, the external Chinese medicine for external Chinese medicine can increase the urine volume of patients and reduce the nitrogen levels of SCr and blood urea. It is an effective method for treating cirrhosis and HRS. Zhu Changquan et al. studied the efficacy of external application of Chinese medicine acupoints combined with octreotide intravenous drops in the treatment of HRS. The results showed that external application of Chinese medicine garlic, Glauber's salt acupoints combined with octreotide intravenous drops can increase the urine volume of HRS patients, improve liver and kidney function, and effectively delay the deterioration of the disease.
3 Summary and Prospect
With the study of the pathophysiological mechanism of HRS, its diagnostic standards and treatment guidelines have been gradually improved. The latest diagnostic criteria for the International Ascites Club in 2015 introduced the concept of AKI, making the diagnosis of HRS more timely and accurately, but it is still challenging and necessary to distinguish HRS from ATN, because vasoconstrictors are not suitable for the treatment of ATN, so it is important to explore more effective biomarkers. At the same time, due to the poor prognosis of HRS and the best treatment currently available is liver transplantation, it is the only cure for HRS. However, there are problems such as difficulty in matching and expensive, so exploring more treatment methods is the focus of solving HRS.
traditional Chinese medicine has achieved good clinical results in the treatment of HRS. In recent years, more and more traditional Chinese medicine doctors have found through clinical trials that traditional Chinese medicine can improve liver and kidney function in many aspects and prolong HRS survival. However, there are few researches on mechanisms at present, so the mechanism of the role of traditional Chinese medicine is still unclear. In the future, conducting large-sample prospective cohort research to clarify the therapeutic role of traditional Chinese medicine, and conducting more in-depth research on drug mechanisms to clarify the therapeutic targets of traditional Chinese medicine is the research direction of traditional Chinese medicine for the treatment of HRS.
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Citations This article
Liang Jiaqi, Liu Wen. Combined diagnosis and treatment of Chinese and Western medicine of liver and kidney syndrome [J]. Journal of Clinical Hepatobiliary Diseases , 2022, 38(9): 1974-1979.
Editor of this article: Liu Xiaohong
official account editor: Xing Xiangyu
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