Ann Hematol (2011) 90:1371–1379 DOI 10.1007/s00277-011-1327-8
REVIEW ARTICLE
New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy Geraldo Bezerra da Silva Junior & Alexandre Braga Libório & Elizabeth De Francesco Daher
Received: 16 July 2011 / Accepted: 25 August 2011 / Published online: 8 September 2011 # Springer-Verlag 2011
Abstract Sickle cell nephropathy is one of the main chronic complications of sickle cell disease (SCD), the most common of the hematological hereditary disorders. Several studies have been performed since the first description of SCD 100 years ago to investigate the mechanisms of kidney involvement in this disease. It has been demonstrated that both glomerular and tubular compartments can be damaged as a direct consequence of SCD, including renal function loss, concentration and acidification deficits, and glomerulopathies. This article highlights the aspects of sickle cell nephropathy pathophysiology and clinical manifestations and describes the most recent advances in the diagnosis and treatment of this disorder. Keywords Sickle cell disease . Sickle cell anemia . Kidney disease . Tubular dysfunction . Kidney failure . Glomerulonephritis G. B. da Silva Junior : E. De Francesco Daher (*) Post-Graduation Program in Medical Sciences, Department of Internal Medicine, Federal University of Ceará, Rua Vicente Linhares, 1198, CEP 60135-270 Fortaleza, Ceará, Brazil e-mail:
[email protected] G. B. da Silva Junior e-mail:
[email protected] G. B. da Silva Junior : A. B. Libório Medicine School, Health Sciences Center, University of Fortaleza, Fortaleza, Ceará, Brazil A. B. Libório e-mail:
[email protected] A. B. Libório Post-Graduation Program in Public Health, University of Fortaleza, Fortaleza, Ceará, Brazil
Introduction Sickle cell disease (SCD) is the most common hematologic hereditary disorder in humans, with a worldwide estimated prevalence of 7% [1]. SCD is characterized by vasoocclusive episodes due to erythrocyte sickling, hemolytic anemia, and increased susceptibility to infections [2, 3]. Chronic organ damage can be observed, including abnormalities in the central nervous system, bone and joints, cardiovascular system, lungs, gastrointestinal tract, and kidneys, with a high mortality, depending on the involved organ [1]. Renal involvement in sickle cell disease includes a variety of glomerular and tubular disorders [4]. It can be found in both patients with sickle cell anemia and sickle cell trait [1, 5] and it is associated with increased mortality [6]. Abnormalities in urinary volume and density have already been described in the first official SCD case reported in medical literature [7]. There is a tendency of hemoglobin S (HbS) to polymerize in the renal medullary region due to its low local oxygen pressure, low pH, and high osmolarity, which favors the erythrocyte dehydration [8–10]. The erythrocyte sickling in the intracapillary space increases blood viscosity in the renal medulla and can cause thrombosis in the vasa recta, manifesting as hematuria due to vessel rupture, renal infarction, and papillary necrosis [9]. Recent studies suggest the participation of oxidative stress in the pathophysiology of sickle cell nephropathy, demonstrating that oxygen reactive species and the products of its oxidative reactions are potential markers of renal involvement severity [11]. The renin–angiotensin intra-renal system also seems to contribute to the pathophysiology of sickle cell nephropathy [12]. Renal abnormalities have been observed in experimental studies with transgenic mice. These abnormalities showed a
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significant association with age and included multiple cortical cysts, tubular hyperplasia, mild to severe nephropathy, and glomerulonephritis [13]. There is also evidence of the association between age and renal involvement in human SCD [14].
Urinary concentration abnormalities The inability to concentrate urine to its maximum (hyposthenuria) as a response to water deprivation is an early finding in sickle cell nephropathy. It has been observed as early as 6–12 months after birth and can be corrected with blood transfusions until the second decade of life [12, 15]. The urinary concentration deficit is the most common tubular dysfunction in SCD and can be observed even in patients with sickle cell trait, with the severity being associated with HbS levels [16, 17]. Patients with SCD can concentrate urine only to a maximum of 400–450 mosM/kg after 8–10 h of water deprivation, in comparison with normal subjects who can normally reach a urinary concentration of 900–1, 200 mosM/kg [18]. Patients with higher levels of HbF have a greater ability to concentrate urine [12]. The production of vasopressin is normal in SCD, and the concentration deficit does not respond to the administration of this hormone, so diabetes insipidus can be ruled out as a possible etiology for this disorder [12, 17]. The occurrence of renal medullary fibrosis and permanent destruction of the collecting ducts result in irreversible urinary concentration deficit [19, 20]. The medullary gradient necessary for sodium reabsorption by the collecting ducts is lost in SCD due to erythrocyte sickling and consequent medullary congestion. In general, the diluting urinary ability is maintained because it depends on solute reabsorption by the cortical nephrons, which are not affected in SCD [17]. Recent studies have shown that serum levels of endothelin-1 increase in patients with SCD after a period of water deprivation, which in turn increases free water clearance and antagonizes antidiuretic hormone, favoring the occurrence of diabetes insipidus and subsequent dehydration [21]. Polyuria can be observed as a consequence of urinary concentration deficit [9]. Many patients present with nocturnal enuresis, mainly during childhood, due to the necessity to consume high amounts of water to compensate the deficit [22]. Nocturnal enuresis is reported in 28% to 37% of children with SCD [23]. The urinary concentration deficit can be asymptomatic, unless there is water deprivation, leading to dehydration [17]. Isosthenuria, renal tubular acidosis, and potassium excretion deficit have all been described in SCD and suggest medullary dysfunction [24].
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Urinary acidification deficit The urinary acidification capacity is also affected in SCD, probably resulting from an incomplete form of distal tubular acidosis attributed to the decreased capacity of the collecting duct to maintain hydrogen gradient [4]. Urinary acidification by the distal nephron depends on the maintenance of a high proton gradient between the tubule and the lumen, an energy-dependent process that is compromised due to medullary ischemia in SCD [16, 25]. An incomplete form of renal tubular acidosis has been described in SCD, with the occurrence of hyperchloremic hyperkalemic metabolic acidosis [15]. Acidosis is not apparent in most cases, unless it is associated with kidney failure [4, 17]. The acidification deficit is less frequent than the concentration deficit because acid excretion is regulated mainly by the cortical segments of the collecting duct, and as the defect in SCD occurs in the deeper segments, the mechanisms of urinary acidification are less affected [17].
Glomerular hyperfiltration An increase in renal blood flow and glomerular filtration is frequently observed in SCD, becoming apparent around 1 year after birth and tending to decrease with aging [1, 26, 27]. In a study with adult SCD patients (mean age of 42 years), a creatinine clearance higher than 120 mL/min/ 1.73 m [2] was found in 14.9% of cases [28]. A higher prevalence (76%) of glomerular hyperfiltration can be found among children with SCD [29]. Glomerular hyperfiltration is involved in the pathogenesis of glomerular disease and kidney failure in SCD [25]. The increase in renal blood is stimulated by the production of prostaglandins, released in response to medullary ischemia, and by the synthesis of nitric oxide, leading to glomerular hyperfiltration [18]. The administration of indomethacin to SCD patients significantly decreased glomerular hyperfiltration, which did not occur in normal subjects, demonstrating the participation of prostaglandins in hyperfiltration pathogenesis in SCD [8]. The kinin– kallikrein system also seems to be involved in hyperfiltration. The production of bradykinins can contribute to vasodilation and glomerular blood flow increase [30]. The urinary excretion of kallikrein was measured in a study with 73 SCD children and showed a significant correlation with albuminuria [31]. There is evidence of creatinine hypersecretion in the proximal tubule in SCD [32], which can make the diagnosis of hyperfiltration difficult. Extremely low creatinine levels and glomerular hyperfiltration are common findings in young patients with SCD [24]. A recent study carried out with Jamaican SCD patients showed that these patients had
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lower blood pressure when compared to controls, associated with normal or supranormal GFR and effective renal plasma flow. Albuminuria higher than 20 μg/min was found in 26% of cases, and a higher GFR was observed in patients with albuminuria, showing that high glomerular flows cause renal damage in SCD [33].
Glomerular diseases Glomerular involvement in SCD generally manifests as edema, albuminuria, and normal levels of complement [34]. Proteinuria is described in 15% to 40% of patients with SCD, and its risk factors include advanced age and low hemoglobin levels [12, 14, 29, 35, 36]. The incidence of proteinuria and glomerulopathies tends to increase with age in patients with SCD [35]. An association between albuminuria and cystatin C levels was observed in a study with 165 SCD patients, in which 72% of patients with proteinuria had increased cystatin C levels [37]. Microalbuminuria is more frequent in patients with sickle cell anemia than in patients with sickle cell trait [38]. A high prevalence of proteinuria was observed in a study with 300 SCD patients followed in the USA, where high levels of albuminuria were found in 68% of cases [39]. The prognosis of patients with proteinuria is not good, and around two of three patients develop chronic kidney disease [34, 39]. Albuminuria is a marker of glomerular involvement and precedes the development of kidney failure [39]. The occurrence of hematuria can be a result of postinfectious glomerulonephritis. Nephrotic syndrome is reported in 20% to 40% of cases, and it was already documented in adolescents and adults with SCD [1, 17, 24, 35]. The pathogenesis of glomerulonephritis in SCD seem to be related to immune complex deposition due to streptococcal infections or deposition of antigens from the tubular epithelium as membranoproliferative glomerulonephritis has been found in patients with SCD [8]. Sickle erythrocyte aggregation can also be involved in glomerulonephritis as it tends to distend glomerular capillaries and arterioles leading to hyperfiltration and possible sclerosis [34]. Tissue ischemia also contributes to glomerular injury in SCD [40]. Advanced age and acute thoracic syndrome have shown to have significant association with glomerular disease in SCD [40]. The renal histological findings already described in SCD includes glomerulomegaly, focal and segmentar glomerulosclerosis (FSGS), including the collapsing variant, immunotactoid glomerulonephritis, thrombotic microangiopathy glomerulopathy, immune complex glomerulopathy, membranoproliferative glomerulonephritis, and amyloidosis [41–46]. In a biopsy review of patients with SCD in France, FSGF was the most frequent glomerulopathy (39%), followed by
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membranoproliferative glomerulonephritis (28%), thrombotic microangiopathy glomerulopathy (17%), and specific sickle cell disease glomerulopathy (17%) [40]. The subtypes of FSGS found in this study were cellular variant, diffuse mesangial hypercellularity, collapsing variant, glomerular tip lesion, and not otherwise specified variant. The thrombotic microangiopathy glomerulopathy is characterized by capillary wall thickening, resulting in narrowing or obstruction of lumens, with basement membrane duplication, mesangiolytic foci, and thrombi in the glomerular capillaries [40]. The specific sickle cell disease glomerulopathy consists of glomerular hypertrophy, with glomerulomegaly and distended capillaries, without the features of FSGS, membranoproliferative glomerulonephritis, or microangiopathy glomerulopathy [40]. IgM and C3 deposits were identified in the cases of FSGS; IgG, IgM, IgA, C3, and C1q in the cases of membranoproliferative glomerulonephritis; IgM and IgG in the cases of microangiopathy glomerulopathy; and no deposits in the cases of specific sickle cell disease glomerulopathy [23, 40]. The renal biopsy can also demonstrate hemosiderin deposits, hemorrhagic areas and focal necrosis, inflammatory interstitial infiltrate, edema, fibrosis, tubular atrophy, and papillary infarctions [18]. The electron microscopy shows, in some cases, the presence of electrondense deposits, which represent iron complexes within the lysosome structures in the glomerular region, mainly in the mesagium [8]. The increase in glomerular size can result from glomerular hyperfiltration, which is a common finding in children with SCD. The glomerular involvement in adulthood is associated with albuminuria and progressive renal function loss [1]. Microalbuminuria is described in 46% of SCD children between 10 and 18 years old [47]. Kidney failure The occurrence of kidney failure is described in 5% to 18% of patients with SCD and is associated with increased mortality [48, 49]. Acute kidney injury (AKI) is less frequent than chronic kidney disease (CKD) in SCD and is a result of hypovolemia, sepsis, hepato-renal syndrome, heart failure, renal vein thrombosis, and rhabdomyolysis. Complete recovery of renal function usually occurs with adequate treatment [15, 50]. Dehydration, the most important cause of AKI in SCD, was observed in 4.6% of patients admitted to emergency services in the USA [51] and can be a consequence of urinary concentration deficit in water deprivation situations. The incidence of AKI in vaso-occlusive episodes is low. It was found in 4.3% of 254 acute episodes among 161 patients followed in France [49]. AKI is also found in the setting of multiple-organ failure, in association with other organ failure, including liver and lungs [8].
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CKD is generally diagnosed in patients between 30 and 40 years and is associated with lower survival [12, 15, 52]. In a recent study conducted in Rio de Janeiro, Brazil, 4.3% of patients admitted with SCD presented CKD [53]. In other studies with SCD outpatients in Cuba, USA, and Saudi Arabia, CKD was identified in 5.9%, 11.6%, and 22.5% of cases, respectively [35, 52, 54]. A lower incidence was observed in a study from Senegal, where CKD was identified in 2.6% of 229 adults with SCD [55]. The main clinical manifestations of CKD in SCD include hypertension, proteinuria, and anemia worsening. New biomarkers are promising for the early detection of renal function loss, including cystatin C and tubular injury markers—N-acetylglucosaminidase, β2-microglobulin, and endothelin-1 [1]. Vaso-occlusive history, legs ulcers, osteonecrosis, retinopathy, proteinuria, hematuria, hypertension, and severe anemia were all identified as predictive factors for CKD in SCD [17, 48, 52]. In a recent study from Nigeria, 50% of SCD patients with proteinuria had CKD [36]. The mean survival of patients with CKD and SCD is estimated to be 4 years, even with dialytic treatment [4].
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Hematuria is one of the most common manifestations of sickle cell nephropathy, and in most cases it is macroscopic and painless [4, 17]. It is the most frequent renal abnormality in patients with sickle cell trait [56]. It is estimated that 3% to 4% of patients with sickle cell trait present with at least one episode of hematuria during their lives [57]. A higher prevalence (8.5%) was reported in a cohort of patients with SCD in Saudi Arabia [58]. When persistent, i.e., several repeated episodes, it can represent the so-called renal sickle crisis [17]. The hematuria can originate in one or both kidneys as a result of papillary necrosis or microthrombosis in peritubular capillaries, and it is also associated to infections [4, 15, 17]. Hematuria should be considered as a consequence of SCD after excluding other possible causes, such as urinary tract infections, neoplasms, vascular malformations, vasculitis, glomerulonephritis, and coagulation disturbances [56, 57]. Around 80% of hematuria cases originate in the left kidney, probably due to the higher pressure in the left renal vein, caused by adjacent vessels compression, a “nutcracker-like” fenomenum [17, 18, 57]. Hematuria can also be a result of late transfusion reaction [15].
nation in asymptomatic patients, but it can be associated with macroscopic hematuria and occurs in 15% to 36% of patients with SCD [4, 15, 59]. Testicular infarction was already described in SCD and patients with sickle cell trait, with some cases needing an orchiectomy [23]. There are many cases reported in literature of renal medullary carcinoma in patients with SCD, and the most common presenting symptoms are macroscopic hematuria, weight loss, and abdominal and lumbar pain [60, 61]. The tumor originates in the distal collecting duct epithelium and grows with an infiltrative pattern [61]. A peculiar finding observed in SCD-associated medullary carcinoma is suppurative necrosis, suggestive of microabscesses with epithelial aggregates [62]. The occurrence of renal carcinoma can be related with genetic factors [48]. In a study conducted in Brazil, the mean survival of patients with this complication varied from 4 to 9 months, demonstrating the aggressive pattern of this neoplasm [62]. Patients with SCD have a higher risk of urinary tract infection (UTI) when compared to the general population, and papillary necrosis is an important risk factor. The most frequent pathogens are Escherichia coli, Klebsiella, and Enterobacter sp., and the UTI can be complicated with urosepsis [15, 34]. In a recent study carried out in the USA, urinary tract infection was found in 3.4% of adult SCD patients admitted to emergency rooms [51]. Sepsis was identified in 7.3% of cases from a cohort of 387 SCD patients in Lebanon, and it was the main cause of death directly related to SCD [63]. All urinary infections in SCD should be considered as complicated infections requiring prolonged antibiotic therapy, from 10 to 21 days [15]. In a Brazilian study analyzing hospital admissions due to SCD complications, urinary infection was found in 30.4% of cases and it was associated with higher mortality [53]. Asymptomatic bacteriuria should also be considered as it is an important risk factor for urinary tract infection and renal damage in SCD [64]. Potassium excretion abnormalities have been described in SCD, with subsequent hyperkalemia [1]. Proximal tubular abnormalities, with increased uric acid and sodium excretion, higher reabsorption of phosphate and β2microglobulin, and deficient production of erythropoietin, rennin, and prostaglandins have also been described [34]. Fanconi’s syndrome was reported in SCD, in association with the use of iron chelators, being reversible after drug withdrawal [65]. The pathophysiology of renal involvement in SCD is illustrated in Fig. 1.
Other genitourinary abnormalities in SCD
Diagnosis
Renal papillary necrosis is more frequently found incidentally through imaging exams or microscopic urine exami-
The laboratory features of sickle cell nephropathy include urinary abnormalities, such as lower density, proteinuria,
Hematuria
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Fig. 1 Pathophysiology of sickle cell nephropathy. NSAIDs non-steroidal anti-inflammatory drugs, HF heart failure, RVT renal vein thrombosis, HRS hepato-renal syndrome, NO nitric oxide. Adapted from [9, 12, 48]
hematuria, and creatinine clearance increase. The increase in creatinine clearance is mainly due to renal hyperflow and higher creatinine secretion by the proximal tubules, and it can reach values as high as 160 mL/min. Due to this fact, the creatinine clearance is not a good test to evaluate renal function in SCD. However, with disease progression there can be a reduction in glomerular filtration rate. Hyponatremia and hyperkalemia can be found in SCD, as well as hypoalbuminemia and increase in the levels of urea and creatinine [34]. The equations to estimate glomerular filtration rate do not present a good correlation with laboratory measurements [29]. The usual renal function tests such as serum creatinine and glomerular filtration rate show abnormal results in SCD only when there is extensive renal damage [66]. A recent study by Sundaram et al. [66], with 116 SCD patients, investigated the usefulness of new renal function biomarkers in SCD, including urinary kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), N-acetyl-b-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and transforming growth factor-b1 (TGF-b). KIM-1 and NAG showed a strong association with albuminuria. On the other hand, NGAL, L-FABP, and TGF-b levels did not show any relationship with albuminuria in patients with SCD [66]. Creatinine, usually low in SCD, is not a good marker to assess renal function in SCD, and the equations to estimate glomerular filtration usually overestimate creatinine clearance [12]. Other methods, such as cystatin C, β2microglobulin, and N-acetyl-β-D-glucosaminidase can be
more useful in SCD [18, 28, 37], but more studies are required to establish the best method for renal function evaluation in SCD. In a study with 87 SCD patients, the levels of cystatin C, N-acetyl-β-D-glucosaminidase and β2-microglobulin were increased in 32.1%, 74.7%, and 70.5%, respectively, while the levels of creatinine were increased in only 6.8% of cases, demonstrating the inadequacy of creatinine as a renal function marker in SCD [28]. The levels of cystatin C also seem to correlate with the degree of proteinuria in SCD and can be increased even in patients with normal creatinine levels [37]. The urinary excretion of endothelin-1 is associated with urinary concentration deficit and microalbuminuria and can be an important marker of renal involvement in SCD [21]. There is evidence that combining more than one biomarker for the assessment of renal function improves diagnosis accuracy. A recent study with 26,643 adults in the US general population investigated the combined use of serum creatinine, urine albumin-tocreatinine ratio (ACR), and cystatin C for detection of chronic kidney disease [67]. The hazard ratio for death in the multivariable-adjusted models was 3.3 for participants with CKD defined by creatinine and ACR 3.2 for those with CKD defined by creatinine and cystatin C, and 5.6 for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 16% had CKD detected by ACR or cystatin C. Risk of incident endstage renal disease was higher among those with CKD defined by all markers [67].
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Imaging examinations frequently reveal caliceal cysts, papillary necrosis, and cortical sclerosis. It is important to have in mind that the use of contrast media should be done with caution not only due to its potential nephrotoxicity but also due to a potential increment in blood viscosity, so the levels of HbS must be previously diluted with blood transfusions. The images are usually normal in SCD children. Computed tomography and ultrasound can be useful in the investigation of papillary necrosis, as well as the pyelogram, but always evaluating the risks and benefits of using contrast media [56, 59]. The ultrasound reveals increased diffuse echogenicity in 7% of cases and restricted to renal medulla in 3% of cases [68]. Increased echogenicity can be associated with glomerular diseases in SCD [40]. The presence of increased kidney size can be observed in young adults with SCD, whereas among adults older than 40 years, kidney size can be diminished or even atrophic [34]. It has been demonstrated that the indices of resistivity and pulsatility determined through Doppler ultrasound can be used as early markers of renovascular abnormalities in SCD [69]. Experimental studies show that ultrasound is a potent tool for the evaluation of vascular alterations and vaso-occlusive phenomenon in SCD [70]. Renal biopsy should be considered in cases of significant proteinuria, when glomerular diseases are suspected and in the cases of rapid or unexplained renal function loss. In the cases of isolated hematuria in SCD, renal biopsy is not indicated [71].
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transfusions demonstrated to restore the urinary concentrating ability in children with SCD, but it has the potential to cause iron overload and should be carefully indicated [4]. Renal protection measures, including the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, (ARB) and statins, have demonstrated benefits in slowing kidney disease progression in many situations [73] and can be beneficial for patients with SCD. The use of ACE inhibitors was shown to significantly reduce proteinuria in SCD [1, 4]. The administration of enalapril showed a significant effect in proteinuria reduction [74]. The use of ACE inhibitors and ARB should be carried out with caution due to the risk of hyperkalemia. Patients with SCD are prone to hyperkalemia, as they have potassium excretion deficit, associated with aldosterone deficiency and distal tubular acidosis [12]. The association of ACE inhibitors and hydroxyurea has also shown to be beneficial in sickle cell nephropathy [75]. However, it is still not established whether hydroxyurea alone has a role in Table 1 Summary of therapeutic options for renal complications of sickle cell disease Complication
Therapeutic options
Urinary concentration inability
Adequate fluid intake Blood transfusions Hydrea (?) Avoid factors leading to metabolic acidosis Hydrea (?) ACEi ARBs Hydrea (?) Bosentan (?) NSAIDs ACEi
Urinary acidification inability
Treatment SCD treatment includes preventive measures and three main therapeutic approaches: blood transfusions, hydroxyurea, and stem cell transplantation [1]. The quality of the evidence for sickle cell nephropathy therapies is based primarily on case series rather than randomized clinical trials, so there is no consensus on the best treatment for these complications. The treatment of renal complications in SCD should include an adequate fluid intake to avoid dehydration due to hyposthenuria and parenteral hydration in the cases of renal infarction [34]. The use of non-steroidal anti-inflammatory drugs (NSAIDs) decrease the creatinine clearance, a potential beneficial effect in SCD patients with glomerular hyperfiltration, but these drugs also accelerate the progression of kidney disease and are a potential cause of interstitial nephritis, so their use should be avoided [16]. Bosentan, an endothelial receptor antagonist, has been shown to prevent the occurrence of microvascular renal congestion and systemic inflammation in mice exposed to hypoxia, and it can be a promising drug for the treatment of sickle cell nephropathy [72]. The use of multiple blood
Glomerular hyperfiltration
Glomerular diseases
Renal insufficiency
Hematuria
Urinary tract infections
ARBs Corticosteroids Hydrea (?) Adequate hydration Infection treatment Avoid nephrotoxic drugs Dialysis Erythropoietin Transplantation Adequate hydration Blood transfusions Urine alkalinization Antibiotic therapy for 10 to 21 days
ACEi angiotensin-converting enzyme inhibitors, ARBs angiotensin II receptor blockers, (?) efficacy not yet completely established in sickle cell disease
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the reduction of proteinuria [12]. Some studies have shown that hydroxyurea prevents glomerular hyperfiltration [76]. The treatment of glomerular diseases in SCD is similar to other glomerulopathies. Methylprednisolone pulse therapy was successfully used in cases of SCD-associated membranoproliferative glomerulonephritis, followed by maintenance therapy with oral prednisone [45, 46, 77]. The approach to chronic kidney disease in SCD is also similar to other causes of CKD. Hemodialysis and peritoneal dialysis have been used in SCD, and both were efficient in controlling the disease, mainly when associated with adequate blood transfusion programs [1, 8, 50]. In the USA, approximately 0.1% of patients in chronic dialysis programs have SCD [12]. The use of erythropoietin (EPO) to correct anemia in CKD is an effective therapy, but the hematocrit increment is associated with increase in painful episodes and can also increase blood viscosity [1]. The experience with the use of EPO in SCD is limited. There is evidence that EPO increases the levels of HbF, but its use in SCD is indicated only when a deficiency of this hormone is present, mainly associated with CKD [15]. Patients with significant hematuria should be advised to maintain a high urine output, by oral hydration, and remain at rest. Patients with hematuria lasting more than 1 or 2 weeks or when blood transfusions are required due to excessive blood loss should maintain a high urine output, with combination of isotonic fluids and loop diuretics, and adopt measures to alkalinize urine, with sodium bicarbonate or acetazolamide. These measures modify the acid and hypertonic environment of the medullar region, which favors erythrocyte dehydration, HbS concentration, and its polymerization [15]. Patients are advised to maintain a urinary volume of 2–4 L/day [17, 48]. Diuresis decreases medullary osmolarity and can help decrease erythrocyte sickling in vasa recta, according to what has been observed in experimental studies [78]. The use of desmopressin and aminocaproic acid has been suggested as hemostatic medications, but their use is still not a consensus in SCD [9]. The response to diuretics in patients with tubular defects is not good in SCD [17]. The role of kidney transplantation has yet to be established in SCD due to the limited number of cases described to date and to the problems reported in the post-transplantation period, which included the increase in pain crisis episodes, thrombotic episodes, allograft thrombosis, and relapse of glomerular diseases [4, 79]. The post-transplantation 1-year survival has been reported to be more than 80% [8]. The 10year survival rates have been reported to be more than 50%, which is higher than the survival observed among SCD patients in chronic dialysis programs [17]. Stem cell transplantation was first performed in patients with SCD more than 25 years ago and remains as the only
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curative treatment, with good results and survival rates around 90% in 4 years [1, 10, 80]. Genetic therapy is a promising option for SCD, but there are still limited data on this subject. Some experimental studies have shown a decrease in erythrocyte sickling, improvement in urinary concentrating ability, and synthesis of human β-globin [81]. A summary of all therapeutic options for sickle cell nephropathy can be seen in Table 1.
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