The Crosstalk between Nephropathy and Coagulation Disorder: Pathogenesis, Treatment, and Dilemmas

ABSTRACT The interaction between the kidney and the coagulation system greatly affects each other because of the abundant vessel distribution and blood perfusion in the kidney. Clinically, the risks of complicated thrombosis and bleeding have become important concerns in the treatment of nephropathies, especially nephrotic syndrome, CKD, ESKD, and patients with nephropathy undergoing RRTs. Adverse effects of anticoagulant or procoagulant therapies in patients with nephropathy, especially anticoagulation-related nephropathy, heparin-induced thrombocytopenia, and bleeding, seriously worsen the prognosis of patients, which have become challenges for clinicians. Over the decades, the interaction between the kidney and the coagulation system has been widely studied. However, the effects of the kidney on the coagulation system have not been systematically investigated. Although some coagulation-related proteins and signaling pathways have been shown to improve coagulation abnormalities while avoiding additional kidney damage in certain kidney diseases, their potential as anticoagulation targets in nephropathy requires further investigation. Here, we review the progression of research on the crosstalk between the coagulation system and kidney diseases and systematically analyze the significance and shortcomings of previous studies to provide new sight into future research. In addition, we highlight the status of clinical treatment for coagulation disorder and nephropathy caused by each other, indicating guidance for the formulation of therapeutic strategies or drug development.


INTRODUCTION
As an important part of physiological hemostasis, coagulation is a complex process involving a series of cascade reactions between coagulation factors, which finally transform fibrinogen into insoluble fibrin, causing blood clotting (Figure 1). 1 Abnormalities in coagulation factors lead to coagulation disorders, resulting in thrombosis or bleeding. 1s a blood filter and the most highly perfused organ, the kidney plays an im-portant role in regulating hemodynamics and blood components, which directly affects coagulation processes. 2In fact, thrombosis is common in patients with nephrotic syndrome (NS) or CKD [3][4][5] or patients undergoing RRTs. 6While patients with ESKD are threatened with bleeding. 7owever, improper anticoagulant or procoagulant therapies may induce adverse effects, such as anticoagulation-related nephropathy (ARN), heparin-induced thrombocytopenia (HIT), or bleeding, which trouble clinicians. 8,9Over the decades, researchers have conducted extensive mechanism studies on the crosstalk between nephropathy and coagulopathy, 5,10 which provide guidance for clinical treatment to some extent.However, the complex interactions between the kidney and the coagulation system are still not fully understood.
Currently, there is no review to systematically summarize and analyze the significance and shortcomings of these findings.Therefore, we review the pathogenesis and treatment of coagulation abnormalities in nephropathy, as well as the manifestations and countermeasures of adverse effects resulting from anticoagulant therapies in nephropathy patients.We emphasize the current problems in clinical practice and the corresponding deficiencies in basic research and analyze the direction of future basic research efforts on the basis of existing studies, as well as the improvement programs that could be considered in clinical treatment.

NS
NS refers to a series of kidney diseases with similar clinical and laboratory features, which are mainly characterized by proteinuria, edema, hypercholesterolemia, and hypoalbuminemia.According to different pathological features, NS can be identified as membranous nephropathy (MN), minimal change disease, focal and segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. 11Thromboembolism is the most serious complication of NS, which is life-threatening.The thrombosis incidence is highest in MN (approximately 37%) and lower in other pathological types of NS (with a cumulative incidence of 24%).Venous thromboembolism (VTE) is the most common type of thrombosis, and coronary thrombosis was also detected. 4,11chanism of Thrombosis in NS It was reported that complicated VTE in NS was mainly caused by the disorders of coagulation and fibrinolytic proteins, while arterial thromboembolism primarily resulted from platelet hyperreactivity. 12isorders of the coagulation and fibrinolytic proteins were caused by the breakdown of the permselectivity barrier of the glomeruli capillary wall in the kidney of patients with NS.Low molecular weight anticoagulant proteins were lost from altered glomeruli (Figure 2A), whereas high molecular weight procoagulant proteins (HMWPPs) were retained in the plasma (Figure 2A). 13,14hese processes led to a decrease in the total concentration of proteins that regulate the coagulation system, which enhanced the compensatory synthesis of both low molecular weight anticoagulant protein and HMWPP.The net effect was the accumulation of HMWPP in the blood, resulting in a hypercoagulable state that promoted thrombosis.Clinical data showed that the more severe the NS, the higher the incidence of thrombosis, which was consistent with the above mechanism. 13latelet hyperreactivity in NS was mainly caused by hypoalbuminemia, hyperfibrinogenemia, and hypercholesterolemia (Figure 2B). 15,16Hypoalbuminemia resulted from the loss of albumin (69 kDa) from the altered glomeruli (Figure 2B, top left).Physiologically, albumin inhibited platelet aggregation by binding to arachidonic acid and preventing its metabolism into thromboxane A 2 (TXA 2 ) and endoperoxides.As a consequence, hypoalbuminemia resulted in the excessive production of TXA 2 and endoperoxides, leading to platelet hyperreactivity. 17In addition, hypoalbuminemia also led to the compensatory synthesis of fibrinogen and von Willebrand factors (vWFs) in the liver, resulting in hyperfibrinogenemia that promoted platelet hyperreactivity (Figure 2B, top right). 14ypercholesterolemia was one of the metabolic consequences of NS, which was confirmed as the promotor of platelet biogenesis and activation.It was reported that in various hematopoietic effector cells, membrane receptor signaling pathways located in lipid rafts were enhanced in response to membrane cholesterol accumulation.Therefore, the accumulation of cholesterol in the plasma membrane enhanced platelet biogenesis in the megakaryoblast (Figure 2B, bottom left) and procoagulant signaling transduction in the platelets (Figure 2B, bottom right), which promoted thrombosis.Indeed, numerous clinical studies detected increased platelet count and platelet hyperactivity in patients with NS, which confirmed the important role of platelets in thrombosis in patients with NS. [18][19][20][21][22][23] Prophylactic and Therapeutic Anticoagulant Therapies in NS Prophylactic and therapeutic anticoagulation is necessary for patients with NS, 24,25 while thrombolytic therapy is only considered in patients with massive pulmonary embolism and severe bilateral deep vein thrombosis due to the high risk of bleeding. 13ow-molecular-weight heparin and warfarin are commonly used for prophylactic and therapeutic anticoagulation in patients with NS. 24 But the advantages and disadvantages of these two drugs have not been compared.With the continuous accumulation of clinical data, arterial thromboembolism was also considered to need attention in patients with NS. 24,26 Therefore, antiplatelet agents were used to prevent and treat thromboembolism in patients with NS.The Kidney Disease Improving Global Outcomes guidelines suggested aspirin may be considered for patients with MN. 27 However, the risk of bleeding persists in patients with NS exposed to anticoagulants; thromboembolism risk and bleeding risk must be balanced during anticoagulation processes.As MN is the most common cause of NS, the Kidney Disease Improving Global Outcomes provides an algorithm for the formulation of prophylactic and therapeutic anticoagulant regimens for patients with MN (Figure 3), which might also be referenced for other pathological types of NS. 24,27 In addition, only a few studies reported the effectiveness of direct oral anticoagulants (DOACs) in preventing thrombosis in patients with NS (Table 1 protein binding rates varied greatly among DOACs (Table 1). 33It is still controversial whether DOACs are suitable for patients with NS.Therefore, we do not recommend DOACs as the first choice for anticoagulation in patients with NS.

Extrinsic (tissue factor) pathway Intrinsic (contact activation) pathway
Faced with the current treatment dilemma, novel anticoagulants or antiplatelet drugs are urgently needed for patients with NS.Interestingly, statins were proven to not only ameliorate kidney injury but also prevent thrombosis in patients with NS. 34,35 These efficacies might come from the inhibitory effect of stains on hypercholesterolemia, which reversed cholesterol-induced platelet hyperreactivity, as described above.Given the dual therapeutic effects of statins on NS and thrombosis, it may be an ideal choice for antiplatelet in patients with NS.More clinical studies are needed to clarify the benefits and shortcomings of statins in preventing thrombosis.

CKD
CKD develops from a series of underlying kidney diseases.It is characterized by decreased GFR (,60 ml/[minz1.73m 2 ]) and elevated renal injury markers (such as serum creatinine and urea nitrogen).CKD significantly increases the risk of thrombosis, 5 especially in patients complicated with atrial fibrillation (AF), which has been recognized as an important cause of stroke. 36,37chanism of Thrombosis in CKD Elevated thrombosis risk in patients with CKD mainly resulted from coagulation and fibrinolytic protein disorders, endothelial dysfunction, and platelet hyperreactivity.
Coagulation and fibrinolytic protein disorders in patients with CKD were characterized by the upregulation of procoagulant proteins, especially coagulation factor VIII, vWFs, and plasminogen activator inhibitor-I. 38,39However, patterns of change in these proteins were not the same as that in patients with NS.Current views hold that these disorders resulted not only from glomeruli injury-induced accumulation of HMWPPs as in NS (Figure 4A) but also from the release of tissue factor (TF) and coagulation activation caused by inflammation-induced vascular endothelial injury (Figure 4B).
Platelet hyperactivity and endothelial dysfunction were caused by uremic toxins that were mainly derived from the gut microbiota (GM). 40It was reported that the decrease in GFR and impairment of renal tubular secretion in CKD resulted in increased production of nitrogen compounds (such as urea and uric acid) which were excreted partly through the intestine, but no urinary tract.In the gut, urea was converted to ammonium, leading to pH elevation and mucosal damage, resulting in GM disorder (Figure 4C, middle). 40GM disorder caused protein assimilation impairment, promoting the synthesis of uremic toxins. 40These uremic toxins were called thrombolome.Thrombolome can be divided into three groups: dietary tryptophan, phenylalanine/tyrosine, and choline/phosphatidylcholine (Table 2). 40ietary tryptophan can combine with aryl hydrocarbon receptor (AhR) and downregulated stress-induced phosphoprotein 1 homologous and U-box containing protein 1 (STUB1).STUB1 plays an important role in TF degradation, which ubiquitinated and degraded TF in uremia environment. 42Dietary tryptophan-induced downregulation of STUB1 led to retarded TF degradation, which enhanced exogenous coagulation pathways. 49In addition, indoxyl sulfate and indole-3-acetic acid (two kinds of dietary tryptophan) could induce oxidative stress and inflammation, which also promoted platelet activation. 41,43henylalanine/tyrosine includes phenylacetylglutamine, p-cresol sulfate, and p-cresol glucuronide.Phenylacetylglutamine has been demonstrated to induce platelet hyperreactivity by activating a2A-, a2B-, and b2-receptors. 46But the mechanisms of platelet activation induced by p-cresol sulfate and p-cresol glucuronide remain unclear.It was suggested that they might promote platelet activation by promoting the release of phosphatidylserine (PS)-positive microparticles (MPs) from endothelial cells. 47Choline/ phosphatidylcholine includes trimethylamine N-oxide which triggered platelet activation primarily by promoting 1,4,5trisphosphate-mediated Ca 21 release. 481][52] It was also reported that GM disorders may lead to increased vitamin K synthesis, but the evidence remains limited (Figure 4C, middle). 40These processes also contributed to thrombosis.

Management of Thrombosis in CKD
Patients with CKD are prone to AF (with a prevalence of 16%-21%), which greatly increases the risk of stroke. 534][55] Currently, international guidelines permit the use of warfarin and DOACs for patients with CKD. 56,57Dabigatran, apixaban, edoxaban, and rivaroxaban have been extensively reviewed for their safety and efficacy in patients with CKD. 57,58Compared with warfarin, DOACs cause a lower incidence of severe intracranial hemorrhage, eliminating the need for drug monitoring, which simplifies the treatment of patients with CKD with VTE or AF. 59But the differences between DOACs have not been compared.With the continuous decline of renal function, bleeding risk is elevated in patients with CKD because of the accumulation of uremic toxins.Therefore, appropriate dosage adjustments according to renal function are required for warfarin or DOACs used in patients with CKD (see detail in Table 3). 60iven the shorting coming of warfarin and DOACs, novel anticoagulants are urgently needed for patients with CKD.Because the AhR-STUB1-TF axis played important roles in promoting thrombosis (Table 2), blocking the AhR-STUB1-TF axis has been shown to effectively improve hypercoagulable state without increasing the risk of bleeding in patients with CKD. 49Targeting the AhR-STUB1-TF axis to develop anticoagulants may avoid the bleeding risk comes from DOACs, which is a direction worth making efforts in the future.

Mechanism of Bleeding in ESKD
Studies indicated that uremic toxin accumulation-induced platelet dysfunction was the main cause of bleeding in patients with ESKD. 5,61,62As adenylyl cyclase activators, uremic toxins could upregulate cAMP that inhibited platelet calcium mobilization, which suppressed platelet activation (Figure 4D). 63Studies found that uremic toxins could inhibit the synthesis and release of TXA 2 , 5-hydroxytryptamine, and ADP in platelets (Figure 4E), 64,65 which may also be one of the causes of platelet dysfunction, but the underlying mechanism has not been clarified.Besides, uremic toxins have also been shown to inhibit actin, thereby disrupting the platelet cytoskeleton, resulting in platelet contraction, movement, and secretion dysfunction (Figure 4F). 66n addition, uremic toxins could inhibit the binding of GPIIb/IIIa to fibrinogen without affecting the abundance of GPIIb/IIIa on the platelet membrane, resulting in decreased platelet-platelet adhesion and signaling transduction (Figure 4G). 67But unlike GPIIb/IIIa, the glycocalicin subunits of GPIb on the platelet membrane were degraded by uremic toxins, which disturbed the binding of vWFs with GPIb/IX/V, leading to inhibition of platelet-vessel wall adhesion.][69][70] All these effects contributed to bleeding in ESKD.
In addition, patients with ESKD were often accompanied by anemia, 71 which may also be one of the causes of bleeding because erythrocytes are important in moving platelets toward the vascular wall to promote platelet aggregation (Figure 4I). 61Anemia in ESKD is mainly caused by decreased secretion of erythropoietin in the kidney,

Origin
Types Functions Dietary tryptophan Indoxyl sulfate a. Inhibiting endothelial cell proliferation and damaging endothelial progenitor cells by inducing oxidative stress and inflammation 41 b.Increasing TF/FVII levels by upregulating the AhR-STUB1-TF axis 40,42 c.Activating platelets by inducing oxidative stress-mediated p38 MAPK activation 43 Indole-3-acetic acid a. Inducing COX-2 expression by activating AhR/p38 MAPK/NF-kB signaling pathways, which led to inflammation and endothelial injury 44 b.Increasing TF/FVII levels by upregulating the AhR-STUB1-TF axis 40,42 c.Activating platelets by inducing oxidative stress-mediated p38 MAPK activation 43   Only used for the emergency treatment of acute and severe bleeding Rapidly inhibiting bleeding in patients with uremia Therapeutic effects are short-lived, and not all patients respond Carrying the risk of infection 76 Applying DDAVP 61 Controlling bleeding in patients with uremia and preventing bleeding before renal biopsy Intravenously administered at a dosage of 0.3mg/kg can inhibit bleeding within 1 h; the effect lasts for 8 h.Could also be given subcutaneously Could be given by intranasal route which is well-tolerated and safe Repeated administration may cause rapid depletion of vWFs, leading to hypotension, tachycardia, and thrombosis in some cases Transfusion of packed erythrocytes 78 The main means to correct anemia before the use of erythropoiesis-stimulating agent Bleeding time can be shortened by infusion of concentrated erythrocytes to a hematocrit of 30% 61 Blood volume overload, hyperkalemia, iron overload, blood-borne infection, fever, and allogenic sensitization 79 Application of recombinant erythropoietin 78 Maintaining the hemoglobin/hematocrit levels of patients with ESKD 61 Reducing the need for erythrocyte transfusions.
Reducing fatigue and improving quality of life 79 Increased risk of adverse cardiovascular outcomes 79 Iron overload 79 Applying TXA 80 Should only be used in patients with severe, lifethreatening bleeding that has failed to be controlled by other evidence-based treatments A single small dose of TXA (7.5 mg/kg) intravenously could reduce the need for blood transfusion 81 Could be safely used to treat severe hematuria in patients with CKD and PKD 80 Could effectively treat massive hemorrhage of the upper digestive tract in hemodialysis patients 82 Causing ureteral thrombosis and cortical necrosis, leading to acute renal failure.Contraindicated in patients with chronic kidney injuries 83 Carrying the risk of systemic epilepsy because it could cross the blood-brain barrier and is neurotoxic 83 DDAVP, desmopressin; vWFs, von Willebrand factors; TXA, tranexamic acid; PKD, polycystic kidney disease.
shortened lifespan of erythrocytes, and inflammation. 71Because erythropoietin is synthesized primarily in the kidney, renal failure in ESKD results in reduced erythropoietin synthesis and subsequent dyserythrogenesis. 72,73Meanwhile, patients with ESKD were usually accompanied by metabolic disorders of vitamin B12 and folic acid, which further aggravated dyserythrogenesis. 74Shortened lifespan of erythrocytes was primarily caused by uremic toxins.Uremic toxins caused oxidative and inhibited Ca 21 pump in erythrocytes which led to cytoplasm Ca 21 overload, resulting in erythrocyte apoptosis. 73Inflammation inhibited erythropoiesis by inhibiting the synthesis of erythropoietin, upregulating soluble erythropoietin receptors, and inducing erythroid progenitor apoptosis. 71Inflammation also accelerated erythrocyte destruction by activating macrophages. 71In addition, inflammation exhibited inhibition effects on the expression of transferrin and disturbed the ferric metabolism in erythrocytes, which may also be the cause of anemia. 73

Management of Bleeding in ESKD
The managements of bleeding in ESKD are mainly based on its pathogenesis.For platelet dysfunction, dialysis is the first option because it removes uremic toxins from the plasma.Estrogen can also be used, which inhibits the production and release of nitric oxide from vascular endothelial cells, thus enhancing platelet-vessel wall interaction. 75or coagulation disorders, infusion of cryoprecipitate is always applied because it is rich in coagulation factor VIII, fibrinogen, fibronectin, and vWFs. 76Desmopressin is also an ideal choice because it can stimulate the release of vWFs. 77For anemia, transfusion of packed erythrocytes or application of recombinant erythropoietin can be chosen.The benefits and drawbacks of these treatments are shown in Table 4.
In addition, secondary hyperfibrinolysis resulting from the hypercoagulability of CKD is also a concern in patients with ESKD.Fibrinolytic drugs such as tranexamic acid (TXA) have been confirmed to shorten bleeding time and improve platelet function in most patients with ESKD. 84But TXA may accumulate in renal insufficiency and has not been shown to be more effective than commonly used therapies. 85Therefore, it was suggested that intravenous TXA should only be considered in acute cases where other treatments have failed to respond satisfactorily. 85T RRT refers to dialysis and kidney transplantation.Patients undergoing RRT are at high risk of thrombosis. 57,86uring dialysis, the formation of blood clots may block the circulation circuit, interrupting the dialysis process, and even endangering the patient's life. 57hile the formation of graft thrombosis in kidney transplant recipients is one of the main causes of graft loss, which has become a concern for clinicians. 86

Mechanism of Thrombosis in Dialysis
Thrombosis during hemodialysis was mainly caused by excessive activation of the contact pathway of the coagulation system and platelets. 87,88ctivation of the contact pathway during hemodialysis has been demonstrated. 87,88Numerous studies have found significant increases in FXIIa levels in the blood of patients undergoing hemodialysis. 87,88FXIIa led to a surge in the production of thrombin which promoted blood clotting. 87,88Activation of FXII may be related to its contact with artificial surfaces because polyvinyl chloride, polyacrylonitrile, polymethylmethacrylate, cellulose triacetate, cuprophane, and polysulfone have been shown to induce FXII activation and thrombin production. 88However, the mechanism of contact pathway activation has not been well elucidated.
It was only known that the negative charge on the artificial surface was conducive to the activation of FXII to some extent (Figure 5A). 89It was reported that FXII inhibitors, such as corn trypsin inhibitor, exhibited inhibitory effects on thrombin production induced by polyvinyl chloride membrane in whole blood or plasma. 90Therefore, elucidating the mechanism by which artificial surface activates FXII is of great significance for the development of novel anticoagulation agents or artificial surfaces that can effectively avoid thrombosis during hemodialysis.
The changes in platelet function during hemodialysis were complex because they were regulated by artificial surfaces, uremic toxins, and hemodynamics. 57,61,91It was reported that the contact of platelets with the artificial surface directly caused platelet activation and degranulation (Figure 5B). 61,92But artificial surface also led to the loss of platelet membrane glycoproteins at the same time (Figure 5B). 92Therefore, in the process of hemodialysis, a temporary platelet dysfunction usually occurred before platelet activation. 92Meanwhile, uremic toxins that may cause platelet dysfunction were removed during hemodialysis, which reversed platelet dysfunction (Figure 5C). 61In addition, platelets were directly exposed to the roller pump in the extracorporeal circuit; the changes in hemodynamics might induce the formation of microbubbles that promoted platelet activation (Figure 5D). 91These effects resulted in platelet hyperreactivity and thrombosis.
Differently, thrombosis is rare in patients undergoing peritoneal dialysis because of the lack of artificial surfaces. 93

Mechanism of Thrombosis in Kidney Transplantation
The underlying diseases and perioperative treatments may be the causes of thrombosis in kidney transplant recipients. 94efore kidney transplantation, underlying diseases (such as NS) and preoperative treatments (such as dialysis) Inducing overproduction of procoagulant factors 106 OKT3 antibody (antithymocyte/ antilymphocyte globulin) Directly targeting the TCR-CD3 complex, which is presently the most potent agent to treat acute renal allograft rejection 107 Inducing TF expression at the surface of both monocytes and endothelial cells, which activated the extrinsic coagulation pathway 107 Thymoglobulin (antithymocyte/ antilymphocyte globulin)

Inducing lymphocyte depletion in the peripheral blood by activating complement-dependent cell lysis and inducing T-cell apoptosis
Thymoglobulin was not specific for T cells; it contained antibodies directed against platelets, which could activate platelets, inducing thrombosis 108

Mycophenolate mofetil (antimetabolite)
Noncompetitive, reversible inhibiting inosine monophosphate dehydrogenase, which is required for purine synthesis during lymphocyte activation 109 Although mycophenolate mofetil did not affect platelet function, it may act as a cofactor in the coagulation cascade, which promoted thrombosis by facilitating the production of Leiden-mutated FV (which cannot be inactivated by protein C) 109,110 Azathioprine (antimetabolite) Azathioprine is converted into sixmercaptopurine which inhibits DNA synthesis, thereby inhibiting lymphocyte proliferation 111 May induce warfarin resistance by enhancing the synthesis of vitamin K-dependent coagulation factors 111 FVIII, coagulation factor VIII; TXA 2 , thromboxane A 2 ; PAI, plasminogen activator inhibitor; PGE 2 , prostaglandin E 2 ; PGI 2 , prostacyclin; NO, nitric oxide; OKT3, anti-CD3 antibody; TCR, T-cell antigen receptor; FV, coagulation factor V; TF, tissue factor.
always resulted in a hypercoagulable state.Patients with ESKD usually required invasive treatments or experienced arteriosclerosis that led to endothelial injury. 95Besides, the use of diuretics increased blood viscosity and slowed blood flow. 3These disturbances led to coagulation and fibrinolytic system disorders, resulting in thrombosis. 96uring kidney transplantation, physiological factors such as shorter and thinner renal veins, 97 younger ages, and different blood types between recipients and donors may promote graft thrombosis. 98Prolonged ischemia during transplantation may induce acute tubular necrosis with graft edema, leading to thrombosis. 99Operation-induced vascular torsion, anastomotic stenosis, and endothelial injury can also lead to thrombosis. 100 After kidney transplantation, patients usually received immunosuppressive therapies.Many immunosuppressants, such as cyclosporine, tacrolimusand, high doses of pulsed methylprednisolone, anti-CD3 antibody, thymoglobulin, mycophenolate mofetil, and azathioprine have been confirmed to disturb coagulation and fibrinolytic systems or cause vascular dysfunction, which were also an important cause of thrombosis. 101he mechanisms by which these immunosuppressants promoted thrombosis are described in detail in Table 5.

Anticoagulation in Dialysis
Anticoagulation is necessary for patients undergoing continuous RRT (CRRT).At present, guidelines recommend heparin or thrombin inhibitors for anticoagulant treatment in dialysis patients (Table 6). 6,112,115Warfarin is not recommended for dialysis patients with AF because it may induce stroke and bleeding. 116,117However, the application of heparin might cause HIT (the underlying mechanism is shown in Figure 6), 9,118 which is a severe immune response characterized by severe thrombosis with a high mortality rate.Therefore, timely HIT detection is necessary for dialysis patients receiving heparin anticoagulation.But the diagnosis of HIT is complex because it relies on clinical suspicion followed by stepwise testing, which delays the treatment of HIT. 119Inspiring, our team has developed the first HIT antibody assay kit in China that could be used for fast bedside HIT diagnosis, which brought benefits to patients  Heparin bound to PF4 to form the PF4-heparin complex that induced HIT antibody production from B cells.HIT antibodies bound to the PF4-heparin complex to form a PF4-heparin-IgG complex.PF4-heparin-IgG complex interacted with FcgRIIA, which induced platelet activation and secondary PF4 release.This circulation promoted the activation of a large number of platelets, resulting in HIT.Immunosuppressants might inhibit B cells from producing HIT antibodies, which inhibited HIT.HIT, heparin-induced thrombocytopenia; PF4, platelet factor 4.
undergoing CRRT.An effective method to avoid HIT in CRRT is to use throminhibitors, but the irreversibility and narrow therapeutic window limit its application.
Given the defects of heparin and thrombin inhibitors, regional citrate anticoagulation (RCA) has emerged in recent years, which is reversible and more effective in anticoagulation with less bleeding and HIT risk. 120However, excessive RCA treatment might cause metabolic acidosis because of citrate accumulation.As a consequence, calcium monitoring is necessary for patients receiving RCA. 121n addition, DOACs were also used in dialysis patients, but apixaban was the only drug that has been proven to be safely used for acute VTE treatment in dialysis patients.Dabigatran and rivaroxaban are not recommended for dialysis patients because of the lack of insufficient evidence.
In recent years, the benefits of factor XI (FXI) inhibitors in dialysis patients have attracted extensive attention.Different from FX, FXI is only involved in the internal coagulation pathway (as shown in Figure 1).Because the hypercoagulable state during dialysis is mainly affected by internal pathways, targeting FXI may gain more advantages than targeting FX in the anticoagulation treatment. 122Several clinical trials have been conducted on the anticoagulant effects of FXI inhibitors in dialysis patients (Table 7); these inhibitors may be the dawn of dialysis patients in the future.

Anticoagulation in Kidney Transplantation
Guidelines for anticoagulant/antiplatelet treatment in kidney transplant recipients are still lacking, but continuous anticoagulation is necessary because the risk of thrombosis persists. 123parin, low-molecular-weight heparin, and warfarin have been shown to be effective in kidney transplant recipients.Interestingly, unlike dialysis patients, kidney transplant recipients undergoing heparin treatment rarely experienced HIT even if they have a history of HIT.This phenomenon might result from the inhibitory effect of immunosuppressants on the synthesis of HIT antibodies (Figure 6), 124 which indicated that heparin may be safe for kidney transplant recipients.Antiplatelet drugs, including clopidogrel and aspirin, could also be used but is not the first choice because available evidences showed that antiplatelet drugs did not improve graft loss in kidney transplant recipients. 125OACs may not be suitable for kidney transplant recipients because it is cleared by the kidney and has drug interactions with certain immunosuppressants, especially calcineurin inhibitors. 33A Nephropathy IgA nephropathy is an autoimmune nephropathy that is manifested by the deposition of IgA immune complexes in the mesangial region of glomeruli.126,127 Although the incidence of thrombosis is low, many studies have also found hypercoagulable states in patients with IgA nephropathy.128,129

Generation of Hypercoagulable States in IgA Nephropathy
The hypercoagulable state of patients with IgA nephropathy may be associated with excessive accumulation of coagulation factors in injured glomeruli, especially coagulation factor V, coagulation factor VII, FVIII, and FIX. 130,131The deposition of coagulation factors may be secondary to IgA deposition.It was reported that the glomeruli capillary wall offered the first contact with circulating macromolecular IgA1, which triggered the secondary complement deposition and alternative pathway activation.Activation of complement destroyed vascular endothelium, which induced collagen exposure and TF release, resulting in coagulation activation (Figure 7B).MPs originated from leukocytes, red blood cells, and might also contribute to the hypercoagulable states in patients with IgA nephropathy.It was reported that terminal complement complex (C5b-C9) may attack MP-originating cells, pouncing PS to the outer leaflet of the plasma membrane accompanied by the shedding of MPs; MPs promoted thrombin production by providing binding sites for the assembly of the prothrombinase and tenase complexes (Figure 7A). 132Indeed, patients with IgA nephropathy usually showed a high level of PS-positive MPs and increased PS exposure in MP-originating cells. 133It was reported that the addition of MPs derived from patients with IgA nephropathy or normal ECs cultured with serum from patients with IgA nephropathy to MP-depleted plasma containing erythrocytes and leukocytes significantly reduced the median coagulation time of MP-depleted plasma, which could be restored by lactadherin (a PS blocker), 133 confirming the procoagulant roles of MPs in patients with IgA nephropathy.

Benefits of Antithrombotic Agents for
Patients with IgA Nephropathy At present, there are no guidelines indicating the need for anticoagulation in patients with IgA nephropathy.But antithrombotic agents have been widely applied to patients with IgA nephropathy in China and Japan (Table 8). 150everal multicenter randomized controlled trials found that anticoagulants/ antiplatelet drugs significantly ameliorated renal injury caused by IgA immune complex deposition (Table 8). 138,150These effects may be related to the downregulation of MPs by anticoagulants/antiplatelet drugs because MPs could also bind to complement C3 and induce proinflammatory cytokines in IgA nephropathy. 151owever, IgA nephropathy is considered as the most common underlying disease of ARN. 152Warfarin, 153,154 dabigatran, 155,156 and aspirin 157 have been confirmed to induce ARN in patients with IgA nephropathy.Therefore, unnecessary anticoagulation in patients with IgA nephropathy may carry the risk of aggravating kidney injuries.The use of warfarin and DOACs should be minimized if not necessary.

ARN
ARN is defined as AKI caused by oral anticoagulants such as and DOACs. 152,158It is mainly manifested by impairment of the glomeruli filtration barrier with Bowman's space and tubular hemorrhage, resulting in tubular obstruction and occlusion. 159

Pathogenesis of ARN
The pathogenesis of ARN has not been fully elucidated.It was found that dabigatran-treated CKD rats developed ARN phenotypes, which could be enhanced by proteaseactivated receptor (PAR)-1 inhibitor SCH79797. 160These findings suggested that DOACs may be the inhibitor of PARs by inhibiting thrombin production.Because PARs provide nutritional support for endothelial cells, the glomeruli destruction hemorrhage might be caused by the inhibitory effect of DOACs on PARs. 161However, it was also found that application of anticoagulant therapies alone cannot cause ARN, and knockout of PAR or application of PAR-1 inhibitor vorapaxar did not induce ARN in experimental models or human patients. 161,162Clinical data also suggested that DOACs induced ARN only when there was significant nephron reduction, hyperperfusion, and hypertension 163 or acute glomeruli injury. 164Therefore, the current views hold that ARN is the result of a second hit of anticoagulants on fragile glomeruli destroyed by the primary disease. 158

Treatment of ARN
The diagnosis of ARN is shown in Figure 8.However, treatment options for ARN are limited.One of the most effective methods is to closely monitor the patient's coagulation and renal function and adopt effective coping strategies during warfarin or DOAC treatment. 161For patients with ARN, treatment is supportive; control of BP and reduction of anticoagulation were commonly used. 161If the patient is anticoagulated with warfarin, the anticoagulation strategy should be switched to DOACs.If the patient is anticoagulated with DOACs, the dose should be reduced. 158In patients with primary or secondary glomerulopathy without ARN, anticoagulation should be combined with glomerular antiinflammatory therapy to effectively prevent ARN. 158

CONCLUSION
Although the crosstalk between nephropathy and coagulation disorder has attracted the attention of clinicians and researchers for decades, practices and studies in this field are still at a relatively preliminary stage.For thromboembolism, heparin, warfarin, DOACs, and antiplatelet drugs are widely used, but adverse effects such as bleeding, HIT, and ARN have become lingering nightmares for clinicians.Owing to the lack of novel drugs, clinicians only have the option of adjusting the dosage (such as adjusting the dosage of DOACs in patients with CKD), which reduces the therapeutic effects at the same time.For bleeding in patients with ESKD, all treatment options have major defects, but there is no better alternative method at present.Encouragingly, some novel ideals point the direction for future drug development, such as inhibiting hypercholesterolemia in NS, targeting the AhR-STUB1-TF axis in CKD, and targeting FXI in dialysis.These methods bypass the limitations of classical drugs, which might bring benefits to patients with nephropathy.But more novel targets and drugs are urgently needed, which requires the joint efforts of researchers and clinicians.

Figure 1 .Figure 2 .
Figure 1.Coagulation cascade and the targets of anticoagulants.The coagulation process consists of a cascade of coagulation factors.Coagulation is initiated by both intrinsic and extrinsic pathways.In the intrinsic pathway, negatively charged surfaces, such as phospholipids and polyphosphates from activated platelets, activate FXII, triggering cascade reactions that ultimately activate FX.In the extrinsic pathway, tissue injury or inflammatory factors induce the expression of TFs that form complexes with activated FVII, thereby activating FX.Activated FX promotes the production of thrombin, which catalyzes fibrinogen (Fg) to soluble fibrin.FXIII promotes cross-linking of fibrin, resulting in the formation of blood clots.Anticoagulants inhibit thrombosis by disturbing the coagulation cascade.Warfarin inhibits the production of vitamin K-dependent coagulation factors (including FII, FVII, IX, and X) in the liver.Heparin primarily promotes the activity of AT-III.DOACs, including apixaban, edoxaban, and rivaroxaban, function as the inhibitor of FX, while dabigatran is the inhibitor of thrombin.Novel anticoagulants, including ISIS 416858 and BAY2976217, are FXI antisense oligonucleotides, while BAY1213790 is the monoclonal antibody to FXI a .AT-III, antithrombin III; DOAC, direct oral anticoagulant; FVII, coagulation factor VII; FXI, factor XI; FXI a , activated factor XI; TF, tissue factor.

Figure 4 .
Figure 4. Mechanism of thrombosis in CKD and bleeding in ESKD.(A) The injuries in the glomeruli filtration barrier in CKD resulted in the leakage of LMWAPs and retention of HMWPPs, which promoted coagulation.(B) Glomeruli endothelial injuries in CKD led to the release of TF which triggered the extrinsic coagulation pathway.(C) Glomeruli injuries in CKD led to an accumulation of urea and uric acid in the gut, causing GM disorder, which on one hand enhanced the production of uremic toxins, resulting in glomeruli inflammation and injury; on the other hand, promoted vWFs, vitamin K, and 5-HT production.(D) Uremic toxins in ESKD activated AC and promoted cAMP production, which inhibited calcium mobilization, resulting in platelet dysfunction.(E) Uremic toxins and calcium mobilization abnormality inhibited the synthesis and secretion of TXA 2 , 5-HT, and ADP in platelets, leading to platelet dysfunction.(F) Uremic toxins destroyed the cytoskeleton of platelet, which disturbed platelet contraction, inhibiting platelet aggregation.(G) Uremic toxins inhibited platelet-platelet interaction by blocking the combination of fibrinogen (Fg) and GPIIb/IIIa, resulting in platelet aggregation dysfunction.(H) PGI 2 and nitric oxide (NO) induced by uremic toxins and uremic toxins themselves inhibited platelet-endothelium interaction by blocking the combination of vWF and GPIb/IX/V, resulting in platelet aggregation dysfunction.(I) Uremic toxins inhibited platelet-erythrocyte interaction, resulting in platelet aggregation dysfunction.5-HT, 5-hydroxytryptamine; AC, adenylate cyclase; GM, gut microbiota; HMWPP, high molecular weight procoagulant protein; LMWAP, low molecular weight anticoagulant protein; NO, nitric oxide; PGI 2 , prostacyclin; TF, tissue factor; TXA 2 , thromboxane A 2 ; vWF, von Willebrand factor.

a 2 .
5 mg twice daily if two of the three criteria are met: creatinine $1.5 mg/dl, body weight #60 kg, aged 80 years or older.b Application of this dosage in patients with CKD has not been approved by Food and Drug Administration.c The dose is halved if any of the three criteria are met: estimated creatinine clearance of 30 approximately 50 ml/min, body weight #60 kg, concomitant use of verapamil or quinidine.d Estimated creatinine clearance values referenced for dose adjustment of apixaban.e This application is recommended by Kidney Disease Improving Global Outcomes but lacks clinical safety or efficacy data.

Figure 5 .
Figure 5. Mechanism of thrombosis in hemodialysis.(A) Contact between FXII and artificial surface activated the intrinsic pathway, which promoted thrombin production, resulting in enhanced coagulation.The negative charge on the artificial surface might contribute to the activation of FXII.(B) Contact between platelets and artificial surfaces induced platelet degranulation, PS exposure, PS-positive MP shedding, and glycoprotein loss.These effects eventually led to platelet activation and leukocyte, RBC, and platelet aggregation.(C) Hemodialysis cleared uremic toxins that induced platelet dysfunction, which promoted platelet activation.(D) Roller pump in the extracorporeal circuit induces the formation of microbubbles which promoted platelet activation.MP, microparticle; PS, phosphatidylserine; RBC, red blood cell.

Figure 6 .
Figure 6.Mechanism of HIT.Heparin bound to PF4 to form the PF4-heparin complex that induced HIT antibody production from B cells.HIT antibodies bound to the PF4-heparin complex to form a PF4-heparin-IgG complex.PF4-heparin-IgG complex interacted with FcgRIIA, which induced platelet activation and secondary PF4 release.This circulation promoted the activation of a large number of platelets, resulting in HIT.Immunosuppressants might inhibit B cells from producing HIT antibodies, which inhibited HIT.HIT, heparin-induced thrombocytopenia; PF4, platelet factor 4.

Figure 7 .
Figure 7. Mechanism of the generation of hypercoagulable state in IgA nephropathy.(A) The deposited complement attacked PS-positive MP-originating cells, leading to the shedding of PS-riched MPs, which promoted the production of thrombin, resulting in hypercoagulable states.(B) The deposited complement induced endothelial injury, which promoted collagen exposure, TF release, and coagulation factor deposition, resulting in hypercoagulable states.MP, microparticle; PS, phosphatidylserine; TF, tissue factor.

Figure 8 .
Figure 8. Diagnosis of ARN.When AKI occurs in patients undergoing anticoagulant therapy with an INR .3.0, ARN should be considered.The first diagnosis is to identify the cause of AKI by urinalysis, urine electrolytes, and kidney ultrasound.If the cause of AKI is clear, ARN could be excluded.If the cause of AKI is unclear, further diagnosis is needed to determine whether the patient develops hematuria.ARN is diagnosed if the patient develops hematuria.If the patient does not develop hematuria, the ARN is not fully determined, but the patient is always treated as ARN.ARN, anticoagulation-related nephropathy; INR, international normalized ratio.
).But excretion and plasma Figure 3. Algorithm for prophylactic and therapeutic anticoagulation in patients with MN.The formulation of an anticoagulant regimen is determined by serum albumin concentration.If the serum albumin concentration is ,2.5 g/dl (by BCG) or ,2.0 g/dl (by BCP), VTE risk should be considered; if the assessed bleeding risk is low, warfarin is considered for prophylactic anticoagulation, and warfarin or LMWH1aspirin are considered for therapeutic anticoagulation.If the serum albumin concentration is 2.

Table 4 .
Benefits and adverse effects of different therapies for bleeding in patients with ESKD

Table 5 .
Immunosuppressants that induced thrombosis after kidney transplantation

Table 7 .
Clinical trials on the anticoagulation effects of factor XI inhibitors in dialysis patients

Table 8 .
Antithrombotic agents that showed therapeutic effects on IgA nephropathy ) effectively enhanced the therapeutic effects of dipyridamole or ACEi/ARB combined with dipyridamole on patients with progressive IgA nephropathy 136 b.Combining heparin-warfarin (a single morning dose to maintain the thrombotest at 30%-50%) and dipyridamole (5 mg/kgzdays, up to 400 mg/d, po) with prednisolone and azathioprine for 2 yr effectively improved glomerulosclerosis in childhood IgA nephropathy 137 Thrombolysis Urokinase a.A single injection of urokinase induced significant fibrinolytic activity, effectively improving albuminuria and/ or hematuria in patients with IgA nephropathy 146 b.Urokinase significantly reduced deposition of C3 in patients with IgA nephropathy, but did not affect IgA and fibrin deposition 147 c.In patients with severe IgA nephropathy, therapeutic effects of urokinase (100,000 IU/d) combined with benazepril (10 mg/d) were superior to benazepril alone 148 d.Continuous urokinase therapy gained better prognoses than antiplatelet therapies in patients with moderate-to-advanced degrees of IgA nephropathy 149 ip, intraperitoneal injection; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; po, per os.