Intrinsic Causes of Acute Kidney Injury

Anitha Vijayan

Introduction

The overall management of a patient with acute kidney injury (AKI), as well as pre and postrenal AKI was covered in Chapter 7.
Once hemodynamic and postrenal causes of AKI have been excluded, acute renal dysfunction that is intrinsic to the kidneys must be considered.
In the approach to intrinsic AKI, it is helpful to group the etiologies by the site of initial nephron pathology: the microvasculature, the glomerulus, the tubule, or the interstitium (please see Table 8-1). Although significant clinical overlap exists, a few readily attainable clinical findings might suggest the category to which a particular case of intrinsic AKI belongs, including microvascular, glomerular, tubular, and interstitial.
- Microvascular: new or accelerating hypertension with evidence of microangiopathic hemolytic anemia. This will be discussed in Chapter 11. Microvascular injury may also be caused by atheroemboli.
- Glomerular: new or accelerating hypertension and volume overload, heavy proteinuria, and/or significant hematuria, especially if red blood cell casts are present. This will be discussed in Chapters 9 and 10.
- Tubular: urinary sediment containing characteristic tubular cell casts or crystals.
- Interstitial: the presence of pyuria or white blood cell casts.
This chapter will focus on the causes of intrinsic AKI that primarily involves the nonglomerular segments of the nephron.

Microvascular Causes of AKI

Atheroembolic renal disease, malignant hypertension, and scleroderma renal crisis may manifest as an acute decline in renal function due to injury to the small arteries and arterioles supplying the glomeruli as the primary pathologic event.
Special emphasis is given to atheroembolic renal disease because of its increased incidence compared with others in this category. Malignant hypertension, antiphospholipid syndrome (APS), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), preeclampsia, and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, are discussed in detail in Chapters 11 and 15.

Atheroembolic Renal Disease

General Principles

Atheroembolic renal disease refers to AKI that arises from the occlusion of the renal microvasculature from inflammation caused by deposition of lipid debris.¹

Three patterns of disease—acute, subacute, and chronic—may be apparent in atheroembolic renal disease.

TABLE 8-1 CAUSES OF INTRINSIC ACUTE KIDNEY INJURY ACCORDING TO SITE OF PRIMARY INJURY

Microvasculature	Glomerulus	Tubule	Interstitium
Atheroembolic renal disease	Rapidly progressive glomerulonephritis	Crystalline nephropathy	Acute interstitial nephritis
Malignant hypertension		Myeloma kidney	Infiltrative malignancies
Scleroderma renal crisis		Acute tubular necrosis (toxic or ischemic)	Acute pyelonephritis
Antiphospholipid syndrome Preeclampsia/HELLP syndrome HUS/TTP
HELLP, hemolysis, elevated liver enzymes, and low platelets; HUS/TTP, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura.

In the acute setting, there is an abrupt deterioration in renal function occurs 3 to 7 days after the inciting event, usually with multisystem organ involvement from a massive embolic shower.

Epidemiology

Atheroembolic renal disease is most commonly a disease of the elderly white male.
The mean age of presentation is 66 to 70 years and men are affected four times as commonly as women, paralleling the prevalence bias of atherosclerotic vascular disease.
The incidence of clinically significant renal atheroemboli is not well defined. It occurs much more commonly with aortography and aortic surgeries.

Pathophysiology

Although spontaneous atheroemboli may occur, more often there is an inciting event leading to plaque destabilization and distal showering of lipid debris.
In the majority of provoked cases, plaque destabilization occurs from vascular wall trauma during either vascular surgeries or percutaneous endovascular procedures.
The lipid lodges in the small arterioles and incites thrombus formation, causing distal ischemia and infarction. Within days, there may be recanalization of the thrombus and restoration of blood flow, but an inflammatory foreign body arteritis then ensues, leading to progressive fibrosis and eventual obliteration of the vessel lumen. Continued nephron ischemia thus occurs.

Prevention

Preventive measures include secondary prevention of atherosclerotic risk factors.
The possibility of using a radial, brachial, or axillary approach for endovascular procedures needs to be considered, as most atherosclerotic plaques are in the abdominal aorta.

Diagnosis

The main manifestations of atheroembolic disease are listed in Table 8-2.

Patients usually have multiple cardiac disease risk factors, a history of cerebrovascular accidents, or an abdominal aortic aneurysm.

TABLE 8-2 CLINICAL AND LABORATORY FINDINGS IN PATIENTS WITH RENAL ATHEROEMBOLIC DISEASE

Very Common	Common	Uncommon
New onset, accelerated, or labile hypertension Skin findings: cyanotic or ulcerated digits or scrotum, livedo reticularis on back or lower extremities, nodules, and/or purpura Elevated erythrocyte sedimentation rate or C-reactive protein Transient peripheral blood eosinophilia	Microscopic hematuria Proteinuria Mildly elevated creatinine kinase, transaminases, or amylase/lipase Gastrointestinal symptoms: nausea, abdominal pain, and/or gastrointestinal bleeding	Fevers Neurologic deficits Retinal emboli with Hollenhorst plaque visible on retinal examination Hypocomplementemia

The typical patient is noted to have blue or dark red discoloration of the toes associated with increasing creatinine several days after a vascular procedure. Lipid embolism can occur from 3 days to 3 months after the inciting event.
- The skin is the most commonly affected organ, but the reliance on characteristic skin findings (e.g., livedo reticularis, cyanotic changes) for diagnosis may contribute to the underrepresentation of this disease among dark-skinned races.
- Other organ systems such as the gastrointestinal tract and central nervous system may be simultaneously involved.
- The multisystem disease involvement, together with the variable occurrence of eosinophilia and depressed complement levels, may mimic a vasculitis.
Renal histology reveals empty clefts in arcuate and interlobular arteries from the dissolution of lipid from these sites by the fixation process.
- Early lesions display an inflammatory arteritis composed of eosinophils, neutrophils, and macrophages, which is later replaced by a giant cell foreign body reaction with proliferation and fibrosis of the vascular intima. Acutely, the tubules may show signs of acute tubular necrosis (ATN).
- Late in evolution, patchy glomerular sclerosis and tubular atrophy may be visualized in areas supplied by affected vessels. Similar arteriolar inflammation or fibrosis can be found in other tissues, especially the muscle, gastrointestinal tract, and skin.

Treatment

Treatment consists of aggressive supportive care addressing the most common mechanisms of death in the acute multivisceral forms of the disease.
With multivisceral involvement, further anticoagulation or intravascular manipulations should be strictly avoided, perhaps even in the setting of recurrent cardiac ischemia.
RAAS blockade for management of hypertension and proteinuria, and use of statins is beneficial.
If renal replacement therapy (RRT) is required, hemodialysis should be performed without anticoagulation. If this is not possible, peritoneal dialysis can be employed.

Outcome/Prognosis

Patients with renal atheroemboli have poor overall prognosis.
Progression to dialysis dependence occurs in approximately one-third of the patients who survive the initial insult, though a mild improvement in glomerular filtration rate can occur.
In a large study of 354 patients, atheroembolic renal disease resulted in end-stage renal disease and death in 33% and 28% of patients, respectively, after an average follow-up of 2 years.

Other Microvascular Causes of Intrinsic AKI

General Principles

Scleroderma renal crisis refers to a clinical entity of acute and progressive renal dysfunction with worsening hypertension occurring in scleroderma patients. An incompletely understood endothelial cell dysfunction with vascular hyperresponsiveness underlies its pathogenesis, as in the other tissues that scleroderma affects Table 8-3.
In APS, antibodies with specificity for anionic phospholipids or the plasma proteins that bind to them induce activation of platelets and endothelial cells, leading to a procoagulant state. If thrombosis occurs primarily in the microvasculature, this can result in an acute or chronic thrombotic microangiopathy in multiple organs, including the kidney. Macroscopic thrombosis may involve the renal arteries in APS and may mimic the microvascular forms of the disease with acute renal failure and accelerating hypertension.
- Catastrophic APS is said to be present if an additional procoagulant stimulus (e.g., infection, surgery, or withdrawal of anticoagulation) initiates fulminant, predominantly microvascular thrombosis that clinically involves at least three different organ systems in a span of <1 week.
HUS and TTP are syndromes of systemic thrombotic microangiopathy and prominent consumptive thrombocytopenia.
- In HUS, drugs, infections, or toxins initiate endothelial and neutrophil activation or a deficiency in complement regulatory molecules leads to microvascular thrombosis.
- TTP appears to result from the accumulation of large von Willebrand multimers from reduced ADAMTS13 protease activity. The large multimers then initiate platelet aggregation and activation in the small vessels.
Preeclampsia is a syndrome of new or worsening hypertension with proteinuria, occurring in the late stages of pregnancy. Endothelial dysfunction seems to occur from an imbalance of placenta-derived angiogenic and antiangiogenic factors.
HELLP is a more severe variant of preeclampsia in which microangiopathic anemia is more prominent and there is evidence of liver dysfunction.²

Diagnosis

Some of the clinical features that distinguish the diseases in this category of intrinsic AKI are discussed in Table 8-3.
The vasculopathy in these disorders leads to glomerular ischemia, which prompts a vicious cycle of high renin- and angiotensin-induced vasoconstriction, rises in blood pressure, and further glomerular ischemia.
- This is most apparent in scleroderma renal crisis, in which there is prompt reversal of the disease with the initiation of angiotensin-converting enzyme inhibition.
The appearance of accelerating hypertension and worsening renal function is common to all of the diseases in this category of AKI secondary to the shared pathophysiologic mechanism of ischemia, leading to increased renin production.
- Marked hypertension may lead to signs of decompensated heart failure or angina.
- Headaches, altered mental status, seizures, or focal neurologic deficits can be evident from hypertensive encephalopathy or cerebral microvascular occlusions.
- Retinal hemorrhages, exudates, or papilledema may be observed on fundoscopic examination.
Laboratory data may reveal findings consistent with a microangiopathic hemolytic anemia (schistocytosis, elevated lactate dehydrogenase, and reduced haptoglobin).
On urinalysis, hematuria, granular casts, and worsening proteinuria may be present in varying degrees.
Renal histology findings are remarkably similar among the diseases in this category, except that malignant hypertension and scleroderma renal crisis may involve the preglomerular vessels more prominently.
- Early on, fibrinoid necrosis with a paucity of inflammatory infiltrate is seen in the small arteries and arterioles. Thrombi may be visualized in glomerular capillary loops. Glomerular endotheliosis, or swelling of endothelial cells with subendothelial deposition of hyaline material, may be seen in any of these diseases, but is more prominent in preeclampsia.
- Later, the intima displays myxoid thickening and finally undergoes fibrous proliferation, resulting in the typical concentric onion skin lesions that may obliterate the lumen of smaller vessels. There is secondary ischemic sclerosis and dropout of supplied glomeruli and tubules.

Treatment

Basic principles of management are presented in Table 8-3.

Acute Tubular Injury

General Principles

ATN refers to the AKI resulting from either ischemic or toxic injury to the tubules. The common etiologies of ATN are detailed in Table 8-4.

The most commonly studied scenarios for ATN include sepsis, cardiothoracic surgery, iodine-based radiocontrast, and nephrotoxic medications. In most cases, the etiology is considered multifactorial in nature.
Three major components that comprise the diverse pathophysiology of AKI include ischemia, inflammation, and direct tubular damage.

The natural history of ATN progresses through four phases:

Initiation refers to an early phase in which ischemia leads to cell injury.
Extension refers to the phase in which tubular cell polarity is disrupted with a loss of viable and damaged cells into the urinary space, causing tubular casts with obstruction and backleak. Electrolyte transport across the tubular brush border is deranged.

During the maintenance phase, the cells undergo dedifferentiation, fibroblast migration, and proliferation, and result in fully established renal failure.

TABLE 8-3 MICROVASCULAR CAUSES OF INTRINSIC ACUTE KIDNEY INJURY

	Malignant Hypertension	Scleroderma Renal Crisis	Microvascular APS^b	HUS/TTP	Preeclampsia/HELLP
Incidence	Most common microvascular cause of AKI at 2.6 per 100,000 patients per year	10% of patients with scleroderma, almost always within first 5 yrs after diagnosis	25% of patients with primary APS	Eleven cases per million people per year	5% of pregnancies
Risk factors	Longstanding hypertension, black race, abrupt interruption of BP medications, secondary causes of HTN	More extensive and rapidly progressive scleroderma skin involvement, cooler temperature environments, black race, initiation of corticosteroids at high dose, use of cyclosporine	Procoagulant states including a recent thrombotic event, withdrawal of anticoagulation, pregnancy, infection, surgery, and so forth	Infection: enteritis with Shiga toxin–producing bacteria, HIV, pneumococcal infection Drugs: quinine, contraceptives, calcineurin inhibitors, chemotherapeutic medications, thienopyridines Peripartum	Previous preeclampsia or positive family history, primigravid, age >40 or <18, multifetal gestation, previous hypertension or renal disease, diabetes, obesity
Distinguishing clinical features^a		Signs of scleroderma (sclerodactyly, interstitial lung disease, and so forth) are present and usually obvious. Autoantibodies (e.g., anti-Scl-70 or anti-ribonucleic acid polymerase) may be present. A total of 10% of patients may be normotensive at diagnosis	Signs of APS (previous thrombosis in an atypical vessel, infarcts in other vascular beds, livedo reticularis, and so forth) or SLE are present. Lupus anticoagulant or antiphospholipid antibody is present. Thrombocytopenia may be significant. Focal renal cortical atrophy may be evident. Course may be chronic, acute, or fulminant (i.e., catastrophic APS)	Hemolytic anemia and thrombocytopenia is prominent. Fever may be present. ADAMTS13 activity may be low in idiopathic TTP but is variable. Presence of accelerated hypertension is less consistently seen	Elevation in BP can be relatively mild. Usually occurs after 20th week of pregnancy. Evidence of fetal compromise may be evident. Reduction in GFR is usually mild. Proteinuria often becomes nephrotic in later stages. Glomerular endotheliosis is prominent early on
Principles of management	Treatment: Reduce BP by 25% within 2–6 hrs and toward 160/100 mm Hg by 24–48 hrs. Renal function may initially worsen slightly	Prevention: Avoidance of renal ischemia from drugs or volume depletion. At-risk patients should monitor BP closely and if a sustained rise occurs, renal function should be assessed Treatment: Initiate ACEI promptly. Renal function may initially worsen, but continued therapy will allow eventual improvement, with >50% of patients able to stop dialysis	Prevention: Avoidance of precipitants (see Risk factors) +/− aspirin or hydroxychloroquine Treatment: Address underlying precipitant, anticoagulation, +/− antiplatelet therapy, +/− glucocorticoids. If catastrophic APS present, initiate plasma exchange or intravenous immune globulin in addition to above	Treatment: Diarrhea-associated HUS—supportive care alone Atypical HUS—eculizumab (discussed in Chapter 11) TTP—supportive care plus plasma exchange (less desirably, high-dose plasma infusion) +/− corticosteroids	Prevention: Low-dose aspirin in high-risk patients Treatment: Antihypertensive therapy and close mother and fetal monitoring until fetal maturity. Deliver fetus if maturity is reached or severe preeclampsia occurs
^a As all may present with accelerated hypertension and worsening renal function, the clinical features that distinguish the diseases are emphasized. ^b Antiphospholipid antibody syndrome may also present with large-artery thrombosis that may manifest similarly to the microvascular form of the disease. ACEI, angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; APS, antiphospholipid syndrome; BP, blood pressure; GFR, glomerular filtration rate; HELLP, hemolysis, elevated liver enzymes, low platelet count; HTN, hypertension; HUS, hemolytic uremic syndrome; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenia purpura.