Kidney
Introduction
Renal vasculature is commonly involved in atherosclerotic, hypertensive, embolic, inflammatory, and hematologic vascular disorders. Adequate delivery of blood to the glomerular capillary network is crucial for glomerular filtration and overall salt and water balance. Thus, in addition to threatening the viability of renal tissue, vascular injury to the kidney may compromise the maintenance of body fluid volume and composition. It is important to keep in mind the unique nature of the renal microvasculature, in particular the presence of a large network of (glomerular) capillaries which subserves the process of glomerular filtration.
Atherosclerosis
- Renal Vascular Injury in Systemic Atherosclerotic Vascular Disease (AVD)
- Macrovascular Atherosclerotic Disease
- As is the case in other vascular beds, the renal artery and its branches are potential sites for plaque formation, which may lead to ischemic renal disease and hypertension (see below).
- Microvascular Atherosclerotic Disease
- Numerous trials in cardiovascular medicine have focused attention on the clinical significance of the rate of urinary albumin excretion (UAE) as an early and powerful predictor of systemic AVD. As illustrated in Fig. 280-1, while both systemic and renal endothelial beds are subject to oxidant stress, inflammation, and hemodynamic injury, a measurable response (elevated UAE) is detectable in the renal microcirculation years before the emergence of systemic disease and/or adverse events in other vascular beds. The strong correlation between UAE and cardiovascular risk, and the parallel improvements noted in both with pharmacologic therapy, support the emerging concept of the renal circulation as an early detection site for atherosclerotic endothelial injury and an integrated marker of cardiovascular risk.
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- Atherosclerotic Renovascular Disease (ARVD) (Renal Artery Stenosis and Ischemic Nephropathy)
- It is estimated that ~5% of cases of hypertension are caused by renal artery stenosis (RAS). In population-based studies, significant (more than 60%) stenosis is found in 9.1% of men and 5.5% of women over 65. The incidence, however, is considerably higher in those being studied for coronary (19%) or peripheral (35–50%) vascular disease. Autopsy studies in patients dying of stroke revealed that at least 1 renal artery is more than 75% stenosed in 10% of the patients studied. The common cause in the middle-aged and elderly is an atheromatous plaque at the origin of the renal artery. Bilateral involvement is present in half of the affected cases. Established plaques progress in more than 50% of cases over 5 years (15% to total occlusion). Renal hypotrophy is detectable in 20% of affected kidneys. In younger women (15–50 years), stenosis is due to intrinsic structural abnormalities of the arterial wall caused by fibromuscular dysplasia.
- In addition to stimulation of renin release, renovascular disease is associated with increased sympathetic neural activity, resulting in frequently described flushing, loss of nocturnal blood pressure (BP) decrease, autonomic instability, and rapid BP swings. In most patients being evaluated for RAS, glomerular filtration rate (GFR) is less more 60 mL/min, with 85% having stage 3–5 chronic kidney disease. GFR in these ranges is a strong independent predictor of cardiovascular risk. Thus, patients with ARVD are more likely to suffer from stroke, heart failure, or myocardial infarction than to progress to end-stage renal disease.
- Diagnosis
- Diagnostic evaluation for significant RAS should begin with noninvasive approaches. An initial screening test is Doppler ultrasonography, which provides information on blood-flow velocity and pressure waveforms in the renal arteries and, when positive, is helpful (sensitivity is 70% at best). Its limitations, however, include significant operator dependence, technical difficulty in obese patients, and poor sensitivity in the presence of multiple renal arteries, distal stenoses, and total occlusion. Measurement of the intrarenal resistance index (RI) provides valuable information on the extent of parenchymal disease and, hence, on the prognosis for functional recovery following revascularization procedures.
- Absence of compensatory hypertrophy in the contralateral kidney should raise the suspicion of bilateral stenosis or superimposed parenchymal renal disease, most commonly hypertensive or diabetic nephropathy. Because angiotensin-converting enzyme (ACE) inhibitors magnify the impairment in renal blood flow and GFR caused by functionally significant renal artery stenosis, use of these drugs in association with 99mTc-labeled pentetic acid (DTPA) or 99mTc-labeled mertiatide (MAG3) renography enhances diagnostic precision and is of additional predictive value. Gadolinium-enhanced three-dimensional magnetic resonance angiography (MRA) has replaced previous modalities as the most sensitive (more than 90%) and specific (95%) test for the diagnosis of RAS. The most definitive diagnostic procedure is contrast-enhanced arteriography. Intraarterial digital subtraction techniques minimize the requirements for contrast, reducing the risk of renal toxicity.
- Renal Artery Stenosis: Treatment
- When blood pressure is controlled and renal function is preserved, expectant therapy and careful follow-up form the best approach for managing RAS. This approach is justified by the devastating consequences of atheroembolic complications of percutaneous revascularization, including loss of renal function. Despite enthusiasm for revascularization procedures for tight RAS in the early to mid-nineties, the past decade has witnessed a significant change in management strategies, stressing more conservative approaches. Medical therapy is aimed at controlling BP and preserving GFR, and includes typically at least three drugs. Angiotensin antagonists (ACE inhibitors or angiotensin receptor blockers) and diuretics are required in most patients. When goal BPs are achieved, clinical outcomes and survival are comparable for medical and revascularization therapies. Revascularization therapy (angioplasty with stent placement) may improve the chances of attaining goal BP but should be considered only after optimal medical therapy has failed to achieve goal BP, or resulted in a more than 30% increase in serum creatinine. BP control and preservation of renal function following revascularization should not be expected when the RI of the targeted kidney is more than 80%. In experienced hands, the complications of angioplasty or stenting are acceptably low. Clinical studies suggest that percutaneous revascularization prevents additional deterioration or even improves renal function in selected patients. Despite technical advances in percutaneous renal revascularization, optimal technique is still evolving. Embolic protection devices may prove useful. Table 280-1 lists current indications for revascularization in patients with RAS. Because of safety, cost, and long-term efficacy, surgical repair is now rarely indicated.
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- Atheroembolic Renovascular Disease
- Atheroembolic renal disease is part of a systemic syndrome characterized by cholesterol crystal embolization. Renal damage results from embolization of cholesterol crystals from atherosclerotic plaques present in large arteries, such as the aorta, to small arteries in the renal vasculature. Atheroembolic renal disease is an increasingly common and often underdiagnosed cause of renal insufficiency in the elderly. Autopsy studies identify cholesterol emboli in 2.4–4% of renal tissue samples, but the incidence increases significantly in elderly individuals, especially in those who had undergone abdominal arteriography or surgery. Male gender, older age, hypertension, and diabetes mellitus are important predisposing factors, present in 85% of cases. Patients with cholesterol embolization syndrome also often have a history of ischemic cardiovascular disease, aortic aneurysm, cerebrovascular disease, congestive heart failure, or renal insufficiency. A significant association is present between RAS and atheroembolic renal disease. Inciting events, which include vascular surgery, arteriography, angioplasty, anticoagulation with heparin, and thrombolytic therapy, can be identified in ~50% of cases. Arteriographic procedures constitute the most common cause of cholesterol embolization.
- Clinical manifestations usually appear 1–14 days after an inciting event, but their onset can be more insidious. Systemic manifestations occur in fewer than half of the patients and include fever, myalgias, headache, and weight loss. Cutaneous manifestations, such as livedo reticularis, "purple" toes, and toe gangrene, occur in 50–90% of patients and constitute the most common extrarenal findings. Other targets of cholesterol embolization include the retina, musculoskeletal system, nervous system, and gut. Accelerated or labile hypertension is present in one-half of patients; malignant hypertension has been described. Renal insufficiency is usually subacute and advances in a stepwise fashion over a period of several weeks. Renal failure, however, can be acute and oliguric. Uremic signs and symptoms requiring dialytic therapy develop in 40% of patients, only half of whom recover sufficient renal function to discontinue dialysis after 1 year. Renal infarction secondary to cholesterol embolization is rare. Cholesterol embolic disease in renal allografts has been reported and can be of donor or of recipient origin.
- Laboratory Findings
- In addition to rising blood urea nitrogen (BUN) and creatinine, laboratory findings may include eosinophilia (60–80%), eosinophiluria, leukocytosis, elevated sedimentation rate, anemia, and hypocomplementemia.
- Antemortem diagnosis of atherosclerotic renal emboli is difficult. The demonstration of cholesterol emboli in the retina is helpful, but a firm diagnosis is established only by renal biopsy. Histologic examination of the occluded vessels reveals biconvex needle-shaped clefts representing the sites of cholesterol crystal deposition. The cholesterol crystals themselves are removed by the usual solvents of tissue fixation but can be visualized in frozen sections of fresh tissue as birefringent crystals under polarized light. They may also be seen in asymptomatic skeletal muscle or skin. Atheroembolic renal disease is associated with a 64–81% mortality rate.
- Atheroembolic Renal Disease: Treatment
- No effective therapy for atheroembolic renal disease is available. Withdrawal of anticoagulation may be beneficial. In some patients, kidney function improved even after a prolonged period of renal insufficiency. Cholesterol-lowering agents may also improve outcome. An aggressive therapeutic approach with patient-tailored supportive measures may be associated with more favorable clinical outcome. Numerous reports suggest a beneficial effect for steroid therapy, but controlled studies are lacking.
- Thromboembolic Renovascular Disease
- Thrombosis of the major renal arteries or their branches is an important cause of deterioration of renal function, especially in the elderly. It is often difficult to diagnose and, therefore, requires a high index of suspicion. Thrombosis may occur as a result of intrinsic pathology in the renal vessels (posttraumatic, atherosclerotic, or inflammatory) or as a result of emboli originating in distant vessels, most commonly fat emboli, emboli originating in the left heart (mural thrombi following myocardial infarction, bacterial endocarditis, or aseptic vegetations), or "paradoxical" emboli passing from the right side of the circulation via a patent foramen ovale or atrial septal defect. Renal emboli are bilateral in 15–30% of cases.
- The clinical presentation is variable, depending on the time course and the extent of the occlusive event. Acute thrombosis and infarction, such as follows embolization, may result in sudden onset of flank pain and tenderness, fever, hematuria, leukocytosis, nausea, and vomiting. If infarction occurs, renal enzymes may be elevated, namely aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase, which rise and fall in the order listed. Urinary LDH and alkaline phosphatase may also increase after infarction. Renal function deteriorates acutely, leading in bilateral thrombosis to acute oliguric renal failure. More gradual (i.e., atherosclerotic) occlusion of a single renal artery may go undetected. A spectrum of clinical presentations lies between these two extremes. Hypertension usually follows renal infarction and results from renin release in the peri-infarction zone. Hypertension is usually transient but may be persistent. Diagnosis is established by renal arteriography.
- Acute Renal Arterial Thrombosis: Treatment
- Management options for acute renal arterial thrombosis include surgical intervention, anticoagulant therapy, intrarenal tissue plasminogen activator, percutaneous rheolytic thrombectomy, conservative and supportive therapy, and control of hypertension. The choice of treatment depends mainly on (1) the condition of the patient, in particular the patient's ability to withstand major surgery; and (2) the extent of renovascular occlusion and amount of renal mass at risk of infarction. In general, supportive care and anticoagulant therapy are indicated in unilateral disease. In acute bilateral thrombosis, medical and surgical therapies yield comparable results. About 25% of patients die during the acute episode, usually from extrarenal complications.
Renal Vascular Injury in Hypertension
Whether it is "essential" or of known etiology, hypertension results in development of intrinsic lesions of the renal arterioles (hyaline arteriolosclerosis) that eventually lead to loss of function (nephrosclerosis).
- "Essential" Hypertension (Arteriolar Nephrosclerosis)
- Arteriolar nephrosclerosis is seen in patients who are hypertensive (BP more than 150/90 mmHg) for an extended period of time but whose hypertension has not progressed to a malignant form (described below). Such patients, usually in the older age group, are often discovered to be hypertensive on routine physical examination or as a result of nonspecific symptomatology (e.g., headaches, weakness, palpitations).
- The characteristic pathology is in the afferent arterioles, which have thickened walls due to deposition of homogeneous eosinophilic material (hyaline arteriolosclerosis). Narrowing of vascular lumina results, with consequent ischemic injury to glomeruli and tubules.
- Physical examination may reveal changes in retinal vessels (arteriolar narrowing and/or flame-shaped hemorrhages), cardiac hypertrophy, and possibly signs of congestive heart failure. Renal disease may manifest as a mild to moderate elevation of serum creatinine concentration, microalbuminuria, or proteinuria.
- "Malignant" Hypertension
- Patients with long-standing hypertension or patients not previously known to be hypertensive may develop malignant hypertension characterized by a sudden (accelerated) elevation of BP (diastolic BP often more than 130 mmHg) accompanied by papilledema, central nervous system manifestations, cardiac decompensation, and acute progressive deterioration of renal function. The absence of papilledema does not rule out the diagnosis in a patient with markedly elevated BP and rapidly declining renal function. The kidneys are characterized by a flea-bitten appearance resulting from hemorrhages in surface capillaries. Histologically, two distinct vascular lesions can be seen. The first, affecting arterioles, is fibrinoid necrosis, i.e., infiltration of arteriolar walls with eosinophilic material including fibrin, thickening of vessel walls, and, occasionally, an inflammatory infiltrate (necrotizing arteriolitis). The second lesion, involving the interlobular arteries, is a concentric hyperplastic proliferation of the cellular elements of the vascular wall with deposition of collagen to form a hyperplastic arteriolitis (onion-skin lesion). Fibrinoid necrosis occasionally extends into the glomeruli, which may also undergo proliferative changes or total necrosis. Most glomerular and tubular changes are secondary to ischemia and infarction. The sequence of events leading to the development of malignant hypertension is poorly defined. Two pathophysiologic alterations appear central in its initiation and/or perpetuation: (1) increased permeability of vessel walls to invasion by plasma components, particularly fibrin, which activates clotting mechanisms leading to a microangiopathic hemolytic anemia, thus perpetuating the vascular pathology; and (2) activation of the renin-angiotensin-aldosterone system at some point in the disease process, which contributes to the acceleration and maintenance of BP elevation and, in turn, to vascular injury.
- Malignant hypertension is most likely to develop in a previously hypertensive individual, usually in the third or fourth decade of life. There is a higher incidence among black men. Presenting symptoms are usually neurologic (dizziness, headache, blurring of vision, altered states of consciousness, and focal or generalized seizures). Cardiac decompensation and renal failure appear thereafter. Renal abnormalities include a rapid rise in serum creatinine, hematuria (at times macroscopic), proteinuria, and red and white blood cell casts in the sediment. Nephrotic syndrome may be present. Elevated plasma aldosterone levels cause hypokalemic metabolic alkalosis in the early phase. Uremic acidosis and hyperkalemia eventually obscure these early findings. Hematologic indices of microangiopathic hemolytic anemia (i.e., schistocytes) are often seen.
- Hypertension: Treatment
- Control of hypertension is the principal goal of therapy. The time of initiation of therapy, its effectiveness, and patient compliance are crucial factors in arresting the progression of benign nephrosclerosis. Untreated, most of these patients succumb to the extrarenal complications of hypertension. In contrast, malignant hypertension is a medical emergency; its natural course includes a death rate of 80–90% within 1 year of onset, almost always due to uremia. Supportive measures should be instituted to control the neurologic, cardiac, and other complications of acute renal failure, but the mainstay of therapy is prompt and aggressive reduction of BP, which, if successful, can reverse all complications in the majority of patients. Presently, 5-year survival is 50%, and some patients have evidence of partial reversal of the vascular lesions and a return of renal function to near-normal levels.
Renal Vascular Injury in Systemic Diseases
Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP)
HUS and TTP, consumptive coagulopathies characterized by microangiopathic hemolytic anemia and thrombocytopenia, have a particular predilection for the kidney and the central nervous system. Previously, the overlap in clinical manifestations had prompted investigators to regard the two syndromes as a continuum of a single disease entity. Recent evidence, however, points to clearly distinct molecular basis for their pathophysiology.
Renal Involvement
Evidence of renal involvement is present in the majority of patients with HUS/TTP. Microscopic hematuria (78%) and subnephrotic proteinuria (75%) are the most consistent findings. Male sex, hypertension, prolonged anuria, and hemoglobin levels less than 10 g/L at onset are associated with a higher risk of renal sequelae in children. Gross hematuria is rare. More than 90% of patients with HUS have significant renal failure, one-third of whom are anuric. The mean duration of renal failure is 2 weeks. Severe acute renal failure or anuria occurs in less than 10% of cases of classic TTP. The degree of elevation of BUN on presentation may be a prognostic indicator in patients with HUS/TTP.
Pathology
The characteristic lesion in HUS/TTP is thrombotic microangiopathy. Microthrombi are demonstrated in renal arterioles and capillaries. In TTP, microthrombi are composed predominantly of platelet aggregates and a thin layer of fibrin and stain strongly for von Willebrand factor (vWF), which has been implicated in its pathogenesis. In contrast, microthrombi in HUS contain predominantly fibrin. Subendothelial hyaline deposits and endothelial cell swelling also contribute to vascular occlusion. Glomerular lesions are ischemic. The glomerular capillary walls are wrinkled, the glomerular tuft may be atrophied, and the Bowman capsule is thickened. Acute cortical or tubular necrosis may occur. Immunofluorescence studies invariably demonstrate fibrinogen along the glomerular capillary walls and in arterial thrombi. Granular deposits of C3 and IgM may be observed in vessel walls and glomeruli. Electron-microscopic studies demonstrate swelling of the glomerular endothelial cells and detachment from the glomerular basement membrane.
Etiology
- HUS
- Two forms of HUS have been described: (1) Diarrhea-associated HUS (D + HUS), the most common form in children, is associated with infection by Shiga toxin–producing Escherichia coli (most commonly O157;H7). This form has an excellent prognosis. Most cases occur in summer and autumn. (2) In contrast, non-Shiga toxin–associated HUS (D – HUS) typically affects adults but can occur at any age. It occurs in sporadic or familial forms, is noninfective, and is usually precipitated by drugs and pregnancy. Several studies have demonstrated genetic predisposition in atypical HUS, involving two regulatory proteins of the complement alternative pathway: factor H (FH) and membrane cofactor protein (MCP, or CD46).
- TTP
- ADAMTS 13 is a member of the recently recognized ADAMTS (a disintegrin with thrombospondin type 1 motifs) zinc metalloproteinase family that cleaves vWF complexes and prevents vWF-platelet interaction. A severe deficiency of ADAMTS 13 has been described in patients with TTP. Two forms have been identified: (1) In sporadic TTP, the deficiency appears to be autoimmune suppression of ADAMTS 13 by circulating IgG antibodies to the protein. (2) Schulman-Upshaw syndrome (a hereditary deficiency) is characterized by thrombocytopenia and microangiopathic hemolysis soon after birth, responding to plasma infusion. Most patients require plasma infusions every 2–4 weeks. Relapses are often triggered by fever, infection, pregnancy, or surgery.
- Drug-induced HUS/TTP is well recognized in patients receiving chemotherapeutic agents, most commonly mitomycin C (cumulative dose of 20–30 mg/m2). The onset of hemolytic anemia and renal failure is usually sudden, and mortality rate is high despite supportive therapy. Treatment with plasma exchange, glucocorticoids, immunosuppressive agents, and staphylococcal protein A immunoadsorption, however, are successful in some cases. Ticlopidine and clopidogrel use has also been associated with the disease. Cyclosporine-induced TTP was first reported following bone marrow transplantation but is more common in patients receiving renal transplants and other solid organs. In renal allograft recipients, cyclosporine-induced HUS occurs during the first week after transplantation as drug toxicity is dose-related. Renal failure reverses with the cessation of cyclosporine or reduction in its dose.
- HUS/TTP may occur after bone marrow transplantation independent of prior radiation or cyclosporine therapy. TTP is commonly associated with pregnancy. Approximately 10–25% of patients with TTP are women who are either near-term pregnant or in the postpartum period; this is also the time for thrombotic events and the occurrence of preeclampsia, eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). These syndromes are difficult to distinguish from TTP-HUS. Decreased activity of ADAMTS 13 in late pregnancy may be an additional risk. Finally, thrombotic microangiopathy has been described in conjunction with vascular tumors, acute promyelocytic leukemia, and prostatic, gastric, and pancreatic carcinomas.
Hemolytic Uremic Syndrome: Treatment
Supportive measures—including dialysis, antihypertensive medications, blood transfusions, and management of neurologic complications—have improved survival in patients with HUS/TTP. Adequate fluid balance and bowel rest are important in treating typical HUS associated with diarrhea. Antibiotics to treat infection caused by Shiga toxin–producing E. coli O157:H7 have been found to increase the risk of overt HUS by 17-fold, likely by favoring the acute release of large amounts of preformed toxin or by providing selective advantage to E. coli O157. Among the therapeutic modalities used to treat patients with HUS/TTP, plasma exchange (plasmapheresis combined with fresh-frozen plasma replacement) is currently the treatment of choice and is superior to plasma infusion alone. Plasmapheresis may remove the recently identified inhibitory autoantibodies against vWF protease from the circulation and supply larger amounts of the protease enzyme. Plasma exchange should be performed daily until remission is achieved, remission being normalization of platelet count, or resolution of neurologic symptoms, or both. Hemoglobin level, percent schistocytosis, reticulocyte count, and renal indices do not appear to be determinants of initial response to therapy, as they may be abnormal for an undefined period after remission. Continuation of plasma exchange for several sessions after remission has been advocated to prevent relapses. Severe renal insufficiency resulting from HUS/TTP often requires dialysis. Renal transplantation has also been performed. HUS/TTP may recur in up to 17% of transplanted patients, independent of cyclosporine use. Higher recurrence rates have been reported for familial HUS.
Scleroderma (Progressive Systemic Sclerosis)
Renal involvement in scleroderma can present in one of two ways, depending on whether malignant hypertension is superimposed on the renal pathology: (1) Persistent urinary abnormalities and an indolent clinical course characterized by proteinuria (15–36%), hypertension (24%), and mild azotemia (15%). Anti-RNA POL3 antibodies are strongly associated with scleroderma renal disease. (2) Scleroderma renal crisis (SRC) is a rapid deterioration in renal function, usually accompanied by malignant hypertension, oliguria, proteinuria, fluid retention, microangiopathic hemolytic anemia, and central nervous system involvement. It occurs in 10% of patients, most commonly in the first 4 years following diagnosis, particularly in patients with diffuse cutaneous involvement, 25% of whom develop SRC. SRC may occur in patients with previously undemonstrable or slowly progressive renal disease. Untreated, it leads to chronic renal failure within days to months. A significant association exists between antecedent glucocorticoid therapy and the development of SRC.
Scleroderma: Treatment
In SRC, ACE inhibitors have improved 5-year survival from 10% to 65%. Some 60% of SRC patients who receive ACE inhibitors require no dialysis (or temporary dialysis) with a survival rate at 8 years of 80–85%, similar to scleroderma patients who do not develop renal crisis. More than half of patients with SRC who require dialysis and are treated aggressively with ACE inhibitors are able to discontinue dialysis 3–18 months later, suggesting that patients should continue ACE inhibitor therapy even after beginning dialysis. Angiotensin receptor antagonists have not proven to be a satisfactory substitute for ACE inhibitors in patients with SRC. SRC patients who progress to end-stage renal disease can undergo hemodialysis or peritoneal dialysis, the latter being occasionally limited by compromised peritoneal clearance. A decrease in graft and overall survival has been noted in scleroderma patients following renal transplantation, as well recurrence of progressive sclerosis in the transplanted kidney, particularly in patients with aggressive disease.
Sickle Cell Nephropathy
Sickle cell disease causes renal complications as a result of sickling of red blood cells in the microvasculature. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction (papillary necrosis). Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.
In addition to the intrarenal microvascular pathology described above, the sickle cell disease in young patients is characterized by renal hyperperfusion, glomerular hypertrophy, and hyperfiltration. Many of these individuals eventually develop a glomerulopathy leading to glomerular proteinuria (present in as many as 30%) and, in some, the nephrotic syndrome. Co-inheritance of microdeletions in the -globin gene ( thalassemia) appear to protect against the development of nephropathy and are associated with lower mean arterial pressure and less proteinuria.
Mild azotemia and hyperuricemia can also develop. Advanced renal failure and uremia occur in 10% of cases. Pathologic examination reveals the typical lesion of "hyperfiltration nephropathy," namely, focal segmental glomerular sclerosis. This finding has led to the suggestion that anemia-induced hyperfiltration in childhood is the principal cause of the adult glomerulopathy. Nephron loss secondary to ischemic injury also contributes to the development of azotemia in these patients.
In addition to the glomerulopathy described above, renal complications of sickle cell disease include cortical infarcts leading to loss of function, persistent hematuria, and perinephric hematomas. Papillary infarcts, demonstrable radiographically in 50% of patients with sickle trait, lead to an increased risk of bacterial infection in the scarred renal tissues and functional tubule abnormalities. Painless gross hematuria occurs with a higher frequency in sickle trait than in sickle cell disease and likely results from infarctive episodes in the renal medulla. Functional tubule abnormalities such as nephrogenic diabetes insipidus result from marked reduction in vasa recta blood flow, combined with ischemic tubule injury. This concentrating defect places these patients at increased risk of dehydration and, hence, sickling crises. The concentrating defect also occurs in individuals with sickle trait. Other tubule defects involve potassium and hydrogen ion excretion, occasionally leading to hyperkalemic metabolic acidosis and a defect in uric acid excretion which, combined with increased purine synthesis in the bone marrow, results in hyperuricemia.
Management of sickle nephropathy is not separate from that of overall patient management , In addition, however, the use of ACE inhibitors has been associated with improvement of the hyperfiltration glomerulopathy. Three-year graft and patient survival in renal transplant recipients with sickle nephropathy is diminished as compared to those with other causes of end-stage renal disease.
Renal Vein Thrombosis (RVT)
Thrombosis of one or both main renal veins occurs in a variety of settings (Table 280-2). Nephrotic syndrome accompanying membranous glomerulopathy and certain carcinomas seems to predispose to the development of RVT, which occurs in 10–50% of patients with these disorders. RVT may exacerbate preexisting proteinuria but is infrequently the cause of the nephrotic syndrome.
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The clinical manifestations depend on the severity and abruptness of its occurrence. Acute cases occur typically in children and are characterized by sudden loss of renal function, often accompanied by fever, chills, lumbar tenderness (with kidney enlargement), leukocytosis, and hematuria. Hemorrhagic infarction and renal rupture may lead to hypovolemic shock. In young adults RVT is usually suspected from an unexpected and relatively acute or subacute deterioration of renal function and/or exacerbation of proteinuria and hematuria in the appropriate clinical setting. In cases of gradual thrombosis, usually occurring in the elderly, the only manifestation may be recurrent pulmonary emboli or development of hypertension. A Fanconi-like syndrome and proximal renal tubular acidosis have been described. RVT is a potential cause of early graft dysfunction following renal transplantation, and its incidence may be decreased with prophylactic low-dose aspirin. The definitive diagnosis can only be established through selective renal venography with visualization of the occluding thrombus. Short of angiography, Doppler ultrasound, contrast-enhanced CT, and MRI often provide evidence of thrombus.
Renal Vein Thrombosis: Treatment
Treatment consists of anticoagulation, the main purpose of which is prevention of pulmonary embolization, although some authors have also claimed improvement in renal function and proteinuria. Encouraging reports have appeared concerning the use of streptokinase. Spontaneous recanalization with clinical improvement has also been observed. Anticoagulant therapy is more rewarding in the acute thrombosis seen in younger individuals. Nephrectomy is advocated in infants with life-threatening renal infarction. Percutaneous mechanical thrombectomy is effective in some cases.