11 - 329 Thrombotic Renovascular Disorders

329 Thrombotic Renovascular Disorders

Adulterants in unregulated herbal and traditional medicaments pose a threat of toxic interstitial nephritis, as exemplified by aristolochic acid contamination of herbal slimming preparations. Contamination of food sources with toxins, such as an outbreak of nephrolithiasis and acute kidney injury from melamine contamination of infant milk formula, poses a continuing risk. Large-scale exposure to aristolochic acid remains prevalent in many Asian countries where traditional herbal medicine use is common. Although industrial exposure to lead and cadmium has largely disappeared as a cause of CIN in developed nations, it remains a risk for nephrotoxicity in countries where such exposure is less well controlled.

New endemic forms of chronic kidney disease continue to be described. In particular, nephropathies with features of CIN have been increasing in prevalence among Pacific coastal plantation work­ ers in Central America (Mesoamerican nephropathy), Sri Lanka (Sri Lankan nephropathy), and southern India (Uddanam nephropathy). Together, these disorders have been called chronic interstitial nephritis of agricultural communities (CINAC) or chronic kidney disease of unknown etiology (CKDu) and may be related to repetitive episodes of heat exposure, dehydration, and volume depletion in the field work­ ers. However, toxins, pesticides, and infective agents also remain as possible etiologic agents. Global warming and regional temperature variability have been proposed as contributors to these newly described forms of kidney disease, and tens of thousands of lives have been lost due to ESRD in these resource-poor areas in which renal replacement therapy is often not an option. PART 9 Disorders of the Kidney and Urinary Tract ■ ■FURTHER READING Eckardt KU et al: Autosomal dominant tubulointerstitial kidney disease: Diagnosis, classification, and management: A KDIGO con­ sensus report. Kidney Int 88:676, 2015. Johnson RJ et al: Chronic kidney disease of unknown cause in agricul­ tural communities. N Engl J Med 380:1843, 2019. Perazella MA, Rosner MH: Drug-induced acute kidney injury. Clin J Am Soc Nephrol 17:1220, 2022. Praga M et al: Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant 30:1472, 2015. Seethapathy H et al: The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors. Clin J Am Soc Nephrol 14:1692, 2019. Elisabeth M. Battinelli, Rebecca L. Zon

Thrombotic

Renovascular Disorders The renal circulation is complex and is characterized by a highly perfused arteriolar network, reaching cortical glomerular structures adjacent to lower-flow vasa recta that descend into medullary segments. This chapter examines primary disorders of the microvessels, many of which are associated with thrombosis and hemolysis. Disorders of the larger vessels, including renal artery stenosis and atheroembolic disease, are discussed elsewhere (Chap. 289). THROMBOTIC MICROANGIOPATHY Thrombotic microangiopathy (TMA) is a pathologic lesion character­ ized by endothelial cell injury in the terminal arterioles and capillaries. Platelet and hyaline thrombi causing partial or complete occlusion are integral to the histopathology of TMA. TMA is usually accompanied by microangiopathic hemolytic anemia (MAHA) with its typical features of thrombocytopenia and schistocytes, but not always. In the kidney,

TMA is characterized by swollen endocapillary cells (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis, and a membra­ noproliferative pattern in the glomerulus. Fibrin thrombi may extend into the arteriolar vascular pole, producing glomerular collapse and at times cortical necrosis. In kidneys that recover from acute TMA, secondary focal segmental glomerulosclerosis may develop. Throm­ botic vascular diseases include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, scleroderma renal crisis, antiphospholipid syndrome, preeclampsia/ HELLP (hemolysis, elevated liver enzymes, low platelet count) syn­ drome, HIV infection, cancer-associated TMA, and microvascular disease associated with COVID-19. ■ ■HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC THROMBOCYTOPENIC PURPURA HUS and TTP are the prototypes for MAHA. Historically, HUS and TTP were distinguished mainly by their clinical and epidemiologic differences. TTP develops more commonly in adults and was thought to have more neurologic complications, while HUS occurs more frequently in children, particularly when associated with hemorrhagic diarrhea. However, atypical HUS (aHUS) can have its first appearance in adulthood, and neurologic involvement can be as common in HUS as in TTP. Currently, HUS and TTP can be differentiated etiologically and treated according to their specific pathophysiologic features. Hemolytic-Uremic Syndrome  HUS is loosely defined by the presence of MAHA and renal impairment. At least four variants are recognized. The most common is Shiga toxin–producing Escherichia coli (STEC) HUS, which is also known as D+ (diarrhea-associated) HUS or enterohemorrhagic E. coli (EHEC) HUS. Most cases involve children <5 years of age, but adults also are susceptible, as evidenced by a 2011 outbreak in northern Europe. Diarrhea, often bloody, precedes MAHA within 1 week in >80% of cases. Abdominal pain, cramping, and vomiting are frequent, whereas fever is typically absent. Neurologic symptoms, including dysphasia, hyperreflexia, blurred vision, memory deficits, encephalopathy, perseveration, and agraphia, often develop, especially in adults. Seizures and cerebral infarction can occur in severe cases. STEC HUS is caused by the Shiga toxins (Stx1 and Stx2), which are also referred to as verotoxins. These toxins are produced by certain strains of E. coli and Shigella dysenteriae. In the United States and Europe, the most common STEC strain is O157:H7, but HUS has been reported with other strains (O157/H–, O111:H–, O26:H11/H–, O145:H28, and O104:H4). After entry into the circulation, Shiga toxin binds to the glycolipid surface receptor globotriaosylceramide (Gb3), which is richly expressed on cells of the renal microvasculature. Upon binding, the toxin enters the cells, inducing inflammatory cytokines (interleukin 8 [IL-8], monocyte chemotactic protein 1 [MCP-1], and stromal cell–derived factor 1 [SDF-1]) and chemokine receptors (CXCR4 and CXCR7); this action results in platelet aggregation and the microangiopathic process. Streptococcus pneumoniae can also cause HUS. Certain strains produce a neuraminidase that cleaves the N-acetylneuraminic acid moieties normally covering the ThomsenFriedenreich antigen on platelets and endothelial cells. Exposure of this cryptic antigen to preformed IgM results in severe MAHA. aHUS or complement-mediated HUS is the result of complement dysregulation. The complement dysregulation can be congenital or acquired. The affected patients often have low C3 and normal C4 levels characteristic of alternative pathway activation. Factor H deficiency, the most common defect, has been linked to families with aHUS. Factor H competes with factor B to prevent the formation of C3bBb and acts as a cofactor for factor I, which proteolytically degrades C3b. More than 70 mutations of the factor H gene have been identified. Most are missense mutations that produce abnormalities in the C-terminus region, affecting its binding to C3b but not its concentration. Other mutations result in low levels or the complete absence of the protein. Deficiencies in other complement-regulatory proteins, such as fac­ tor I, factor B, membrane cofactor protein (CD46), C3, complement factor H (CFH)–related protein 1 (CFHR1), CFHR3, CFHR5, and thrombomodulin, have also been reported. Finally, an autoimmune variant of aHUS, DEAP (deficiency of CFHR plasma proteins and

CFH autoantibody positive) HUS, occurs when an autoantibody to factor H is formed. DEAP HUS is often associated with a deletion of an 84-kb fragment of the chromosome that encodes for CFHR1 and CFHR3. The autoantibody blocks the binding of factor H to C3b and surface-bound C3 convertase. Renal injury is often severe, resulting in end-stage renal disease. The severity of the renal injury and recurrence after kidney transplant depend on the complement regulatory protein. Thrombotic Thrombocytopenic Purpura  Traditionally, TTP is characterized by the pentad of MAHA, thrombocytopenia, neuro­ logic symptoms, fever, and renal failure; however, <5% of individuals with immune-mediated TTP will have the full pentad. The patho­ physiology of TTP involves the accumulation of ultra-large multim­ ers of von Willebrand factor as a result of the absence or markedly decreased activity of the plasma protease ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. TTP is now defined as MAHA associated with ADAMTS13 activity of <5–10%. These ultra-large multimers form clots and shear erythro­ cytes, resulting in MAHA; however, the absence of ADAMTS13 alone may not by itself produce TTP. Often, an additional inflammatory trig­ ger (such as infection, surgery, pancreatitis, or pregnancy) is required to initiate clinical TTP. This may be mediated by human neutrophil peptides that inhibit cleavage of von Willebrand factor by ADAMTS13. TTP can be congenital from ADAMTS13 mutation (cTTP) or acquired from autoantibody against ADAMTS13 protein (iTTP). cTTP, also known as Upshaw-Schülman syndrome, is characterized by congenital deficiency of ADAMTS13. cTTP can start within the first weeks of life but, in some instances, may not present until adulthood, especially during pregnancy. Both environmental and genetic factors are thought to influence the development of cTTP. Plasma transfusion is an effective strategy for prevention and treatment. In iTTP, autoantibody to ADAMTS13 (IgG or IgM) either increases its clearance or inhibits its activity. Data from the Oklahoma TTP/HUS Registry suggest an iTTP incidence rate of 2.9 cases/106 patients in the United States. The median age of onset is 40 years. The incidence is more than nine times higher among blacks than nonblacks. Like that of systemic lupus erythemato­ sus, the incidence of iTTP is nearly three times higher among women than among men. If untreated, iTTP has a mortality rate exceeding 90%. Even with modern therapy, 20% of patients die within the first month from complications of microvascular thrombosis. Drug-induced TMA is a recognized complication of treatment with some chemotherapeutic agents, immunosuppressive agents, and quinine. Two different mechanisms are now recognized. Toxic or endothelial damage (pathologically similar to that of HUS) is the main cause of the TMA that develops in association with chemotherapeu­ tic agents (e.g., proteasome inhibitors [bortezomib, carfilzomib, and ixazomib], mitomycin C, and gemcitabine) and immunosuppressive agents (cyclosporine, interferon, sirolimus, and tacrolimus). This process is usually dose-dependent. Alternatively, TMA may develop as a result of drug-induced autoantibodies. This form is less likely to be dose-dependent and can, in fact, occur after a single dose in patients with previous exposure (quinine). ADAMTS13 deficiency is found in fewer than half of patients with clopidogrel-associated TTP. Quinine appears to induce autoantibodies to granulocytes, lymphocytes, endo­ thelial cells, and platelet glycoprotein Ib/IX or IIb/IIIa complexes, but not to ADAMTS13. Quinine-associated TTP is more common among women. TMA has also been reported with drugs that inhibit vascular endothelial growth factor, such as bevacizumab; the mechanism is not completely understood. TREATMENT Hemolytic-Uremic Syndrome/Thrombotic Thrombocytopenic Purpura Treatment should be based on pathophysiology. iTTP and DEAP HUS respond to the combination of plasma exchange and predni­ sone. In addition to removing the autoantibodies, plasma exchange with fresh-frozen plasma replaces ADAMTS13. Twice-daily plasma

exchanges with administration of rituximab may be effective in refractory cases. The use of caplacizumab, a monoclonal antibody fragment that binds to the A1 domain of von Willebrand fac­ tor, blocking its interaction with platelets, was recently shown to improve platelet count recovery and reduce the composite risk of death, disease exacerbation, and thromboembolic events. It is now approved for use in iTTP in conjunction with plasma exchange and immunosuppressive therapy. Plasma infusion is usually sufficient to replace the ADAMTS13 in cTTP. Plasma exchange should be con­ sidered if larger volumes are necessary. Additionally, newer medica­ tions are being studied and utilized in TTP, such as caplacizumab, a humanized monoclonal antibody fragment that binds to von Willebrand factor and blocks its interaction with platelet glycopro­ teins. Caplacizumab can be considered as an additive medication, especially in those with severe features of TTP or in cases with con­ tinued thrombocytopenia that does not respond to initial therapy.

Plasma infusion/exchange is effective in certain types of aHUS because it replaces complement-regulatory proteins. Eculizumab and ravulizumab, anti-C5 monoclonal antibodies, are approved for use in aHUS and have been shown to abort MAHA and improve renal function. Antibiotics and washed red cells should be given in neuraminidase-associated HUS, and plasmapheresis may be helpful; however, plasma and whole-blood transfusion should be avoided since these products contain IgM, which may exacerbate MAHA. Combined factor H and ADAMTS13 deficiency has been reported. The affected patients are generally less responsive to plasma infusion, an outcome that illustrates the complexity of the management of these cases. CHAPTER 329 Thrombotic Renovascular Disorders Drug-induced TMA secondary to endothelial damage typically does not respond to plasma exchange and is treated primarily by discontinuing the use of the agent and, if refractory, a trial of C5 inhibitors. Similarly, STEC HUS should be treated with supportive measures as plasma exchange has not been found to be effective. Antimotility agents and antibiotics increase the incidence of HUS among children, but azithromycin may decrease the duration of bacterial shedding in adults. ■ ■HEMATOPOIETIC STEM CELL TRANSPLANTATION–ASSOCIATED THROMBOTIC MICROANGIOPATHY Hematopoietic stem cell transplantation (HSCT)–associated TMA develops after allogeneic HSCT, with an incidence of ~8%. Etiologic factors include conditioning regimens, immunosuppression, infec­ tions, and graft-versus-host disease. Other risk factors include female sex and human leukocyte antigen (HLA)–mismatched donor grafts. HSCT-TMA usually occurs within the first 100 days of HSCT. Table 329-1 lists definitions of HSCT-TMA currently used for clinical trials. Diagnosis may be difficult since thrombocytopenia, anemia, and renal insufficiency are common after HSCT. HSCT-TMA carries a high mortality rate (75% within 3 months). The majority of patients have

10% ADAMTS13 activity, and plasma exchange is beneficial in <25% TABLE 329-1  Criteria for Establishing Microangiopathic Kidney Injury Associated with Hematopoietic Stem Cell Transplantation INTERNATIONAL

WORKING GROUP BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK TOXICITY COMMITTEE

4% schistocytes in the blood RBC fragmentation and at least 2 schistocytes per high-power field De novo, prolonged, or progressive thrombocytopenia Concurrent increase in LDH above baseline A sudden and persistent increase in LDH Negative direct and indirect Coombs test Decrease in hemoglobin or increased RBC transfusion requirement Concurrent renal and/or neurologic dysfunction without other explanations Decrease in haptoglobin concentration Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell.

of patients. Discontinuation of calcineurin inhibitors and treatment of infections or sinusoidal obstruction syndrome (if present) are recom­ mended. There are increasing reports of successful use of eculizumab, but clinical trial data are lacking.

■ ■CANCER-ASSOCIATED TMA When MAHA and thrombocytopenia are present, one should assess for evidence of malignancy and consider the diagnosis of cancerassociated TMA. The mechanism of TMA in cancer is thought to be tumor cell obstruction in the microvasculature leading to cell frag­ mentation and platelet consumption: TMAs in cancer can occur on initial diagnosis of the cancer or when the cancer becomes refractory, and have been identified in both solid malignancies and hematologic malignancies. Clinical features, such as bone pain and respiratory symptoms, have been found to occur more in cancer-associated TMA than in TTP. Additionally, compared to immune-mediated TTP, there is no role for plasma exchange, steroids, or other immunosuppression in cancer-associated TMA; instead, the management is treatment of the underlying malignancy. ■ ■HIV-RELATED THROMBOTIC MICROANGIOPATHY HIV-related TMA is a complication encountered mainly before wide­ spread use of highly active antiretroviral therapy. It is seen in patients with advanced AIDS and low CD4+ T-cell counts, although it can be the first manifestation of HIV infection. The presence of MAHA, thrombocytopenia, and renal failure is suggestive, but renal biopsy is required for diagnosis since other renal diseases are also associated with HIV infection. Thrombocytopenia may prohibit renal biopsy in some patients. The mechanism of injury is unclear, although HIV can induce apoptosis in endothelial cells. ADAMTS13 activity is not reduced in these patients. Cytomegalovirus co-infection may also be a risk factor. Effective antiviral therapy is key, while plasma exchange should be limited to patients who have evidence of TTP. PART 9 Disorders of the Kidney and Urinary Tract ■ ■PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA) MAHA can also be present in scleroderma renal crisis, which is also characterized by acute kidney injury, abrupt onset of hypertension, and a normal urine sediment, although each of these aspects is not required for the diagnosis. Scleroderma renal crisis occurs in 12% of patients with diffuse systemic sclerosis but in only 2% of those with limited systemic sclerosis. Although MAHA is present in more than half of patients, coagulopathy is rare. Retinopathy and encephalopathy may accompany the hypertension. Salt and water retention with micro­ vascular injury can lead to pulmonary edema. Cardiac manifestations, including myocarditis, pericarditis, and arrhythmias, denote an espe­ cially poor prognosis. The renal lesion in scleroderma renal crisis is characterized by arcu­ ate artery intimal and medial proliferation with luminal narrowing. This lesion is described as “onion-skinning” and can be accompanied by glo­ merular collapse due to reduced blood flow. Histologically, scleroderma renal crisis is indistinguishable from malignant hypertension, with which it can coexist. Fibrinoid necrosis and thrombosis are common. Before the availability of angiotensin-converting enzyme (ACE) inhibitors, the mor­ tality rate for scleroderma renal crisis was >90% at 1 month. Introduction of renin-angiotensin system blockade has lowered the mortality rate to 30% at 3 years. Nearly two-thirds of patients with scleroderma renal cri­ sis may require dialysis support, with recovery of renal function in 50% (median time, 1 year). Glomerulonephritis and vasculitis associated with antineutrophil cytoplasmic antibodies and systemic lupus erythematosus have been described in patients with scleroderma. An association has been found with a speckled pattern of antinuclear antibodies and with antibodies to RNA polymerases I and III. Anti-U3-RNP may identify young patients at risk for scleroderma renal crisis. Anticentromere antibody, in contrast, is a negative predictor of this disorder. Because of the overlap between scleroderma renal crisis and other autoimmune disorders, a renal biopsy is recommended for patients with atypical renal involvement, especially if hypertension is absent. Treatment with ACE inhibition is the first-line therapy unless contraindicated. The goal of therapy is to reduce systolic and diastolic

blood pressure by 20 mmHg and 10 mmHg, respectively, every 24 h until blood pressure is normal. Additional antihypertensive therapy may be given once the dose of drug for ACE inhibition is maximized. Angiotensin II receptor antagonists are less effective at preventing renal failure; thus, they are only recommended if the patient is intolerant of ACE inhibitors. ACE inhibition alone does not prevent scleroderma renal crisis, but it does reduce the impact of hypertension. In addition, it has been observed that patients on ACE inhibitors have a higher renal recovery rate after initiation of dialysis, and thus, ACE inhibi­ tors are continued even after starting dialysis. Intravenous iloprost has been used in Europe for blood pressure management and improve­ ment of renal perfusion. Kidney transplantation is not recommended for 2 years after the start of dialysis since delayed recovery may occur. Bosentan (endothelin-1 antagonist) and eculizumab have both been investigated for use in this disease. ■ ■ANTIPHOSPHOLIPID SYNDROME Antiphospholipid syndrome (APLS) (Chap. 369) can be either primary or secondary, with the most common rheumatologic association being with systemic lupus erythematosus. It is characterized by a predisposi­ tion to systemic thrombosis (arterial and venous) and/or recurrent fetal loss mediated by antiphospholipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and/or anti-β-2 glycoprotein I anti­ bodies (antiβ2GPI). In addition to the antibody laboratory findings, classification criteria based on the 2023 American College of Rheu­ matology and European Alliance of Associations for Rheumatology include clinical features, such as macrovascular venous and arterial thromboses, microvascular thrombotic events, specific obstetric com­ plications, cardiac valve abnormalities, and thrombocytopenia. Being positive for lupus anticoagulant, antiβ2GPI, and anticardiolipin anti­ bodies (“triple positive”) is associated with the highest thrombosis risk. APLS is the leading cause of stroke in patients <45 years old. The vascular compartment within the kidney is the main site of renal involvement. Arteriosclerosis is commonly present in the arcuate and intralobular arteries. In the intralobular arteries, fibrous intimal hyperplasia characterized by intimal thickening secondary to intense myofibroblastic intimal cellular proliferation with extracellular matrix deposition is frequently seen along with onion-skinning. Arterial and arteriolar fibrous and fibrocellular occlusions are present in more than two-thirds of biopsy samples. Cortical necrosis and focal cortical atro­ phy may result from vascular occlusion. TMA is commonly present in renal biopsies, although signs of MAHA and platelet consumption are usually absent. TMA is especially common in the catastrophic variant of antiphospholipid syndrome, which is a life-threatening syndrome characterized by rapid onset of symptoms, multiorgan failure, and severe thrombotic events. Treatment entails lifelong anticoagulation. For most individuals with APLS, warfarin is the preferred anticoagulant over direct oral anticoagulants (DOACs), with an international normalized ratio (INR) goal of 2–3. One can consider DOACs in a few, specific instances, such as a single venous thrombosis event or in those intolerant to warfarin, but never in those with arterial thrombotic events. Providers should have clear risk-benefit discussions with the patient if choosing a DOAC over warfarin given inferiority in many instances. In those with arterial thrombotic events, antiplatelet therapy is often a recommended addi­ tion to warfarin. Catastrophic APLS management includes anticoagu­ lation, glucocorticoids, plasma exchange, and/or IV immunoglobulin (IVIG). Addition of rituximab and eculizumab can be considered, often in the refractory setting, although ongoing studies are evaluating earlier use of these agents. ■ ■HELLP SYNDROME HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a dangerous complication of pregnancy associated with microvascular injury. Occurring in 0.2–0.9% of all pregnancies and in 10–20% of women with severe preeclampsia, this syndrome carries a mortality rate of 7.4–34%. Most commonly developing in the third trimester, 20% of cases occur before week 28, and 30% occur postpartum. Although a strong association exists between HELLP syndrome and preeclampsia,

nearly 20% of cases are not preceded by recognized preeclampsia. Risk factors include abnormal placentation, family history, and elevated levels of fetal mRNA for FLT1 (vascular endothelial growth factor receptor 1) and endoglin. Patients with HELLP syndrome have higher levels of inflammatory markers (C-reactive protein, IL-1Ra, and IL-6) and soluble HLA-DR than do those with preeclampsia alone. Renal failure occurs in half of patients with HELLP syndrome, although the etiology is not well understood. Limited data suggest that renal failure is the result of both preeclampsia and acute tubular necrosis. Proteinuria is present in 86–100% of cases. Renal histologic findings are those of TMA with endothelial cell swelling and occlusion of the capillary lumens, but luminal thrombi are typically absent. How­ ever, thrombi become more common in severe eclampsia and HELLP syndrome. Although renal failure is common, the organ that defines this syndrome is the liver. Subcapsular hepatic hematomas sometimes produce spontaneous rupture of the liver and can be life-threatening. Neurologic complications such as cerebral infarction, hemorrhage, and edema are other potentially life-threatening complications. Nonfatal complications include placental abruption, permanent vision loss due to Purtscher-like (hemorrhagic and vaso-occlusive vasculopathy) reti­ nopathy, pulmonary edema, bleeding, and fetal demise. Many features are shared by HELLP syndrome and MAHA. Diag­ nosis of HELLP syndrome is complicated by the fact that aHUS and TTP also can be triggered by pregnancy; in addition, complement gene mutations and complement pathway dysfunction are common (30–40%) among patients with HELLP syndrome. Patients with antiphospholipid syndrome also have an elevated risk of HELLP syndrome. A history of MAHA before pregnancy is of diagnostic value. Serum levels of ADAMTS13 activity are reduced (by 30–60%) in HELLP syndrome but not to the levels seen in TTP (<10%). Determination of the ratio of lactate dehydrogenase to aspartate aminotransferase may be helpful. This ratio is 13:1 in patients with HELLP syndrome and preeclampsia as opposed to 29:1 in patients without preeclampsia. Other markers, such as antithrombin III (decreased in HELLP syndrome but not in TTP) and D-dimer (elevated in HELLP syndrome but not in TTP), may also be useful. HELLP syndrome usually resolves spontaneously after delivery. Management includes administering magnesium sulfate for seizure prophylaxis and treating hypertension if present. A key component of treatment is delivery; timing of delivery is based on severity of symptoms and age of the fetus. In pregnancies with serious maternal or fetal complications, prompt delivery is recommended. In those without serious complications, the age of the fetus and fetal maturity can help distinguish between prompt delivery or a course of antenatal steroids. Plasma exchange has no benefit in HELLP but may be indicated if TTP has not yet been ruled out. Eculizumab has been reported to be effective in a small number of cases, but dosing, efficacy, and indications remain undetermined. ■ ■POEMS SYNDROME POEMS syndrome is a systemic disease characterized by polyneu­ ropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, with polyneuropathy and monoclonal gammopathy being mandatory major criteria. Peripheral neuropathy often presents with severe motor-sensory deficit. Three other major criteria, at least one of which is required, are elevated vascular endothelial growth factor (VEGF) levels, evidence of Castleman disease, and sclerotic bone lesions. Patients also commonly have elevated IL-6. Another characteristic is that >95% of monoclonal light chain is of the lambda isotype. IgA also makes up ~50% of the monoclonal proteins involved. Organomegaly can involve any organ and often presents as lymphade­ nopathy. Other findings can include skin changes, thrombocytosis, polycythemia, papilledema, and volume overload. POEMS syndrome can occur with Castleman disease. In the kidney, the hypertro­ phy frequently is unilateral. One study suggests the difference in kidney size is due to unilateral contraction; however, a volumetric study showed that enlargement is responsible for the difference in kidney size in some patients. Glomerulomegaly is not uncommon. Lobular appearance, endothelial cell swelling, hypercellularity, mesan­ giolysis, microaneurysm, and glomerular enlargement are reminiscent

of membranoproliferative glomerulonephritis. Most patients present with mild to moderate renal impairment and low-grade proteinuria. Progression to end-stage renal disease is rare.

■ ■SICKLE CELL NEPHROPATHY Renal complications in sickle cell disease result from occlusion of the vasa recta in the renal medulla. The low partial pressure of oxygen and high osmolarity predispose to hemoglobin S polymerization and erythrocyte sickling. Sequelae include hyposthenuria, hematuria, and papillary necrosis (which can also occur in sickle trait). The kidney responds by increasing blood flow and glomerular filtration rate mediated by prostaglandins. This dependence on prostaglandins may explain the greater reduction of glomerular filtration rate by nonste­ roidal anti-inflammatory drugs in these patients than in others. The glomeruli are typically enlarged. Intracapillary fragmentation and phagocytosis of sickled erythrocytes are thought to be responsible for the membranoproliferative glomerulonephritis–like lesion, and focal segmental glomerulosclerosis is seen in more advanced cases. Screening for sickle cell nephropathy should include blood pres­ sure monitoring, urine studies for albumin-to-creatinine ratio, and metabolic panel. Proteinuria is present in 20–30%, and nephroticrange proteinuria is associated with progression to renal failure. ACE inhibitors reduce proteinuria, although data are lacking on prevention of renal failure. Patients with sickle cell disease are also more prone to acute renal failure. The cause is thought to reflect microvascular occlusion associated with nontraumatic rhabdomyolysis, high fever, infection, and generalized sickling. Chronic kidney disease from sickle cell nephropathy is present in 25–33% of patients. Despite the fre­ quency of renal disease, hypertension is significantly lower in patients with sickle cell disease compared to the general population of black individuals. Treatment can include medications, such as hydroxyurea, which has been shown to decrease vaso-occlusive events and lessen albuminuria. Two gene therapies for patients with sickle cell who have recurrent vaso-occlusive episodes and are >12 years old were approved in December 2023. Exagamglogene autotemcel uses CRISPR/Cas9 gene editing to modify BCL11A and increased fetal hemoglobin, whereas lovotibeglogene autotemcel uses lentiviral technology to pro­ duce a modified hemoglobin similar to hemoglobin A. Evaluation of outcomes in these individuals is ongoing. CHAPTER 329 Thrombotic Renovascular Disorders RENAL VEIN THROMBOSIS Renal vein thrombosis either can present with flank pain, tender­ ness, hematuria, rapid decline in renal function, and proteinuria or can be silent. Occasionally, renal vein thrombosis is identified during a workup for pulmonary embolism. The left renal vein is more com­ monly involved, and two-thirds of cases are bilateral. Etiologies can be divided into three broad categories: endothelial damage, venous stasis, and hypercoagulability. Homocystinuria, endovascular intervention, and surgery can produce vascular endothelial damage. Dehydration, which is more common among male patients, is a common cause of stasis in the pediatric population. Stasis also can result from compression and kinking of the renal veins from retroperitoneal processes such as retroperitoneal fibrosis and abdominal neoplasms. Thrombosis can occur throughout the renal circulation, including the renal veins, with antiphospholipid syndrome. Renal vein thrombosis can also be secondary to nephrotic syndrome, particularly membranous nephropathy. Other hypercoagu­ lable states less commonly associated with renal vein thrombosis include proteins C and S, antithrombin deficiency, factor V Leiden, disseminated malignancy, and oral contraceptives. Severe nephrotic syndrome may also predispose patients to renal vein thrombosis. Diagnostic screening can be performed with Doppler ultrasonog­ raphy, which is more sensitive than ultrasonography alone. Computed tomography angiography is almost 100% sensitive. Magnetic resonance angiography is another option but is more expensive. Treatment for renal vein thrombosis consists of anticoagulation and therapy for the underlying cause. Endovascular thrombolysis may be considered in severe cases. Occasionally, nephrectomy may be undertaken for lifethreatening complications. In patients who cannot receive anticoagula­ tion, suprarenal inferior vena cava filters can be considered.