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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 2  |  Page : 249-265
An update on sickle cell nephropathy

King Fahad University Hospital, Dammam University, Al Khobar, Kingdom of Saudi Arabia

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Date of Web Publication11-Mar-2014


Sickle cell disease (SCD) is a major health problem in many countries. Sickle cell nephropathy (SCN) is now a well-characterized entity with specific manifestations, risk factors and prognosis. The presence of sickled erythrocytes in the renal medullary vessels is the hallmark of the disease with a variety of renal complications. Renal manifestations of SCD include renal ischemia, microinfarcts, renal papillary necrosis and renal tubular abnormalities with variable clinical presentations. Proximal tubule dysfunction generally impairs urinary concentration, while more distal tubule dysfunction may impair potassium excretion, leading to hyperkalemia. Glomerular disease with proteinuria may develop due to ischemia and results in a compensatory increase in the renal blood flow and glomerular filtration rate; such hyperfiltration, combined with glomerular hypertrophy, probably contributes to glomerulosclerosis. Acute and chronic kidney disease are the expected outcomes of the disease. Both dialysis and kidney transplantation are effective renal replacement therapies for end-stage renal disease due to SCN, with a higher advantage for transplantation. Whether bone marrow transplantation in the early stage of the disease can halt the progression of SCN is unknown and awaits clinical studies.

How to cite this article:
Alhwiesh A. An update on sickle cell nephropathy. Saudi J Kidney Dis Transpl 2014;25:249-65

How to cite this URL:
Alhwiesh A. An update on sickle cell nephropathy. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2022 Sep 29];25:249-65. Available from: https://www.sjkdt.org/text.asp?2014/25/2/249/128495

   Introduction Top

Sickle cell nephropathy (SCN) is indicated by the presence of sickled erythrocytes in the renal medulla that result in decreased medullary blood flow, ischemia, microinfarcts and papillary necrosis in the kidneys. These pathologic changes result in tubular and glomerular function disturbances that affect blood pressure regulation and water and electrolyte metabolism [Table 1]. Although there are many studies showing that proteinuria, nephritic syndrome, chronic progressive renal failure and acute renal failure syndromes are the outcomes of SCN, the pathogenic mechanisms and potential therapies remain to be elucidated. Platt et al provide the most comprehensive analysis of life expectancy and risk factors for early death in sickle cell disease (SCD); 18% of deaths are ascribed to chronic end-organ involvement, predominantly renal. [1] Patients with SCN who progress to end-stage renal disease (ESRD) have similar survival to those with non-diabetic ESRD. [2] This article reviews the glomerular and tubular disorders associated with SCN and points to relevant pathophysiological and clinical implications.
Table 1: Renal manifestations of sickle cell disease (SCD).

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   Pathophysiology Top

Chronic sickling of blood cells underlies several mechanisms for kidney injury in SCN associated with low O 2 tension, hypertonicity and low pH of the renal medulla that promote the formation of hemoglobin polymers in the red cells with deformation of the sickled cells, and result in an increase in the blood viscosity, functional venous engorgement and interstitial edema, which predispose the renal microcirculation to ischemia and infarction. [3] Obliteration of the medullary vasculature produces segmental scarring and interstitial fibrosis (structural papillectomy), which result in the formation of dilated renal pelvic capillaries and veins. Hematuria may result from rupture of vessels from the early venous engorgement or from the dilated vessels. The development of collateral vessels and their abnormal orientation in the medulla interferes with the countercurrent exchange mechanism, culminating through the years in an irreversible loss of medullary tonicity. [3] Renal cortical blood flow and glomerular filtration rate (GFR) are increased perhaps by the secretion of the medullary vasodilator prostaglandins. [3] Hyperfiltration coupled with glomerular hypertrophy can lead to glomerulosclerosis. [3],[4],[5] Once progression of the glomerular damage is evident, GFR begins to decrease, likely with some contribution from the ingestion of analgesics that can independently induce interstitial nephropathy. [4] Guasch et al [6] documented a pattern of increased dextran permeability in the glomerular basement membrane of SCD patients, with an incremental increase in the pore radius. This would cause a non-selective proteinuria rather than the microalbuminuria associated with hyperfiltration. Bank et al [7] showed that in a transgenic sickle cell mouse model, there is an induction of nitric oxide synthase II (NOS II) in the glomeruli and distal nephron. This enzyme may increase the synthesis of nitric oxide leading to vasodilatation and contribute subsequently to hyperfiltration.

   Hematuria Top

Hematuria is a major alteration detected in individuals with the SCD and sickle cell trait. It is usually described as painless, symptom less, benign and self-limited, but it may also be hemorrhagic and difficult to control. The pathogenesis of hematuria seems to be explained by vascular obstruction in the renal medulla by sickled red blood cells (RBCs), with conesquent extravasation of blood cells [8],[9] [Figure 1]. In 80-90% of the cases, bleeding is unilateral and originates from the left kidney, probably be-cause of the anatomic differences in the kidney venous drainage. [10] Mostofi and associates studied 21 kidneys from patients with SCD that were removed because of massive blood loss and the possibility of renal neoplasm. [11] The absence of gross alterations in most of these kidneys emphasizes the fact that the lesions are inconspicuous and may be easily missed. The most striking change was severe stasis in the peritubular capillaries of both the cortex and the medulla; changes were marked mostly in the medulla and extravasation of blood was observed mainly in the collecting tubules. In 1990, Osegbe described 12 individuals (six with SCD) aged between 12 and 32 years with renal papillary necrosis diagnosed by suggestive findings on excretory urography and manifested by hematuria of 3 days' to 5 months' duration. [12] Bleeding was intense in four patients and moderate in eight patients. Mild lumbar pain and fever occurred at a low frequency. Hematuria originated exclusively from the left side in ten of these patients. Renal medullary carcinoma, although rare, should always be kept in the differential diagnosis, especially in patients with sickle cell trait; renal imaging and urine cytology should be performed in these patients. [13],[14] Gross hematuria occurs in patients who have either heterozygous sickle hemoglobin (Hb-AS, Hb-SC) or homozygous disease (Hb-SS). [15],[16],[17],[18],[19],[20] However, gross hematuria occurs approximately 40 times more commonly in the sickle cell trait than in the homozygous state, and can occur at any age, and is more common in males than in females. [20],[21]
Figure 1: Sickle cell nephropathy. Sickled erythrocytes in capillary loops. (Jones' silver stain with hematoxylin and eosin counter stain.)

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   Renal Papillary Necrosis Top

Renal papillary necrosis (RPN) is a frequent occurrence in both SCD and the sickle cell trait. As a complication of SCN, papillary necrosis has an incidence of 30-40%, [22] and is mediated by the occlusion of the vasa recta of the medullary vessels [Figure 1]. [23] In most patients with SCD, the infarcted areas are small and renal function is not usually immediately affected. [24] Less commonly, the SCD patients may have more widespread necrosis of the papillae due to more extensive infarction. [2] The individual variability in non-SCD genes helps to determine the degree of blood vessel occlusion with infarction. Thus, while HbS is caused by a single mutation, SCD could be a multi-gene disease. [25] This concept may account for the variable severity of disease, including the degree of papillary necrosis, among the SCD patients. The vessel occlusion is also affected by the local production of cytokines. [26] The SCD patients with higher levels of fetal hemoglobin (HbF) or of hemoglobin A 2 have a lower risk for the SS hemoglobin polymerization and, hence, a lower risk for infarction of the papillary tissue with subsequent papillary necrosis. [27] In addition to HbS polymerization, the degree to which sickled RBCs adhere to the vascular endothelium is an important component of the cascade leading to blood vessel occlusion in SCD. [26] Accordingly, the immature and large RBCs are more likely than mature ones to adhere to the vascular endothelium. [26] There is individual variability among SCD patients in their marrow response to the increased RBC destruction that characterizes the SCD; [28] variability in the release of immature RBCs might contribute to the individual variability in the degree of the vaso-occlusive disease, including papillary necrosis. The clinical presentation of the RPN varies from asymptomatic macroscopic hematuria to an acute condition that involves pain, fever and even obstructive acute renal failure (ARF). However, a similar frequency of RPN has been described in symptomatic and asymptomatic individuals (65% and 62%, respectively). This may be at times associated with urinary tract infections (61.5%), continuous or persistent macroscopic hematuria and pain. [29] RPN is most frequently found incidentally during the different renal imaging procedures [intravenous pyelography, [Figure 2], ultrasound, computerized axial tomography scan (CT) and magnetic resonance imaging]. In ultrasound examination, the earliest finding in RPN is the increased echogenicity in the medullary pyramids, [Figure 3]. In later stages, calcification may appear in the medullary pyramids with a typical "garland pattern" surrounding the renal pelvis or a defect in echogenicity in the pyramids due to detachment of the papilla. In cases of uncertainty, helical CT scans are more sensitive than ultrasound for early detection of RPN; however, prophylactic measures, especially volume expansion, must always be practiced to prevent nephrotoxicity from iodinated contrast solutions. [30]
Figure 2: Renal papillary necrosis: Pyelographic image in a patient with sickle cell disease showing central cavities within multiple papillae (arrows).

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Figure 3: Renal papillary necrosis: Renal ultrasound showing increased echogenicity of the medullary pyramids in a patient with sickle cell disease.

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The most detailed analysis of reported series found 131 cases of papillary necrosis in 334 patients with SCD (39%), with an incidence ranging from 23-67% in the individual series. [24] The true incidence of this complication is higher as many cases will be asymptomatic or have only microscopic hematuria that is not evident using imaging procedures. [31] The mean age at discovery was 21 ± 1 years (range, 4-68 years). [24] Papillary necrosis is categorized according to severity as partial papillary or total with sequestrated papillae, and amputated calyces. Totally sloughed papillae may be seen as filling defects in the renal pelvis, ureters or bladder. [24]

   Tubular Abnormalities Top

Proximal tubular dysfunction

Increased reabsorption of phosphate and beta-2 microglobulin, as well as increased secretion of uric acid and creatinine, reflects excessive proximal tubule function, which may account for the overestimation of the true GFR measured with creatinine clearance in patients with the SCD, [32] and cystatin C clearance may be a better indicator. [33],[34] Moreover, with the increased RBC turnover and consequent uric acid overproduction, most patients with SCD are normouricemic; uric acid clearance is greater in these patients. [35],[36] However, urate clearance decreases with age and the incidence of hyperuricemia increases as renal function deteriorates. Maximum tubular reabsorption of phosphate is also increased in patients with SCD; therefore, serum phosphate is elevated in these patients [Table 1]. , Some studies report an increased plasma volume in the non-crisis steady state in the SCD patients. [40],[41],[42] Increased reabsorption of β-microglobulins has also been described.

Distal tubular dysfunction

RBC sickling in the vasa recta is believed to interfere with the countercurrent exchange mechanism in the inner medulla. The resulting impairment of free water resorption manifests clinically as nocturia or polyuria [Figure 4].
Figure 4: Renal medullary changes that lead to hyposthenuria, papillary necrosis and hematuria in sickle cell disease.

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The impaired ability to concentrate urine, termed hyposthenuria, is the earliest manifestation of SCN. [44] The ability to dilute urine remains intact and antidiuretic hormone (ADH) secretion remains normal in SCN patients with hyposthenuria, because the vaso-occlusive process spares the superficial loops of the loop of Henle (which are supplied by peritubular capillaries rather than by the vasa recta).

In patients aged 10-15 years, urinary concentrating capacity may be restored with multiple transfusions of normal RBCs. Conversely, in patients older than 15 years, the concentration defect is often irreversible. [46] An impaired ability to concentrate urine readily leads to volume depletion, especially in warm environments. Intravascular volume depletion potentiates the occurrence of sickle cell crisis and is treated with intravenous fluid hydration using isotonic saline.

Other processes that occur in the renal medulla include urinary acidification and the excretion of potassium [Table 1]. Ischemia involving the renal medulla leads to the inability to maintain a hydrogen ion gradient, causing an incomplete form of distal renal tubular acidosis, which can be associated with aldosterone-independent hyperkalemia. [47],[48] Although the exact mechanism is not clear, medullary blood flow disturbance and hypoxia may result in insufficient energy to maintain the hydrogen ion and electrochemical gradients along the collecting ducts. However, these impairments are usually mild and become clinically apparent only if there is a complicating factor such as potassium or acid loading, intravascular volume depletion or during rhabdomyolysis. [49],[50]

   Blood Pressure Top

The incidence of hypertension among patients with SCD is markedly lower than that observed in the general population (2-6% versus 28%, respectively), and some patients may have lower than normal blood pressure. [51],[52] The proposed mechanisms for this relative hypotension include:

  • Sodium and water wasting due to the medullary defect [41],[49]
  • Systemic vasodilatation compensating for microcirculatory flow disturbances [52]
  • Increased production of prostaglandins and nitric oxide [32]
  • Reduced vascular reactivity. [41]

These observations have important clinical implications that include the possibility that relatively "normal" blood pressure levels actually represent significant hypertension with the attendant risks of adverse cardiovascular outcomes and that severe hypotension may ensue with the use of antihypertensive agents to lower intraglomerular pressure.

   Glomerular Filtration and Renal Blood Flow Top

GFR and renal blood flow (RBF) are increased by as much as 50% in patients with SCD. [53],[54] This is probably related to compensatory hypersecretion of vasodilator prostaglandins during the process of sickling. The filtration fraction is usually decreased, indicating that increases in GFR are not proportional to those of RBF. Anemia per se probably has some influence on these abnormalities as similar changes have been observed in children with β-thalassemia. [55] However, other factors must be involved because transfusion-associated increases in hematocrit do not cause the renal hemodynamic parameters to revert to normal. [55] Bank et al recently studied the mechanism of hyperfiltration in a transgenic sickle cell mouse model and concluded that renal synthesis of nitric oxide by the L-arginine pathway was increased and correlated positively with the GFR. [56] In a more recent study, the exposure of transgenic sickle cell mice to chronic hypoxia resulted in the activation of inducible nitric oxide synthase and superoxide radical and peroxynitrite formation; the consequences of these reactions enhanced apoptosis, ultimately resulting in structural damage. [57] Whether these mechanisms are operative in humans remains to be proved. Both GFR and RBF are normal during adolescence, but are frequently subnormal after the age of 40 years. [58],[59] On the other hand, some patients with Hb-SS in their 40s or even older may have completely normal or even supernormal GFR and RBF. [60] The renal pathological fin-dings in young patients with SCD include glomerular enlargement as well as increased numbers of capillary lumens and epithelial, endothelial and mesangial cells. [61] Other findings may include congestion of capillary loops with sickled erythrocytes and hemosiderin [Figure 1]. GFR and RBF are within the normal range in the sickle cell trait, sickle cell-hemoglobin C disease, homozygote-hemoglobin C disease, hemoglobin C trait and sickle cell β-thalassemia. [62]

   Renal Medullary Carcinoma Top

Renal medullary carcinoma is a highly aggressive malignancy found almost exclusively in young black patients with the sickle cell trait and, less commonly, the SCD. [51],[63],[64],[65],[66] Most patients are younger than 20 years of age at presentation and there appears to be a male predominance in childhood. [63],[64],[65] Genetic linkage is suggested by the young age and tumor aggressiveness and cytogenetic testing has suggested a potential association with various chromosomal anomalies. [65],[66]

Affected patients present with gross hematuria, urinary tract infection, flank pain, an abdominal mass and/or weight loss. [64],[65] Metastatic disease is commonly present at diagnosis; thus, surgical resection is not curative. There is very limited experience in treating disseminated disease, [65],[67],[68] and the prognosis is dismal; survival after diagnosis is usually less than 6-12 months. [63],[65],[67] Thus, hematuria should prompt evaluation for this type of malignancy, particularly among younger patients with SCD or trait. Imaging (usually CT scan and intravenous pyelography) demonstrates a centrally located infiltrative lesion invading the renal sinus with peripheral caliectasis.

The use of hydroxyurea (HU) to treat SCD has raised concern that these patients may have an increased risk of other cancers, but this is unclear. [69],[70],[71]

   Glomerular Abnormalities and Proteinuria Top

The patients with SCD may develop proteinuria and renal failure that progresses into terminal chronic kidney disease (CKD). The renal involvement responsible is a glomerulopathy whose initial marker is albuminuria. The prevalence increases with age, ranging between 21.3% [72] and 28% [73] in patients aged 3-20 years, of which 10.5% of the cases progress to proteinuria within a 20-month follow-up period. In most cases (72%), CKD progresses into renal failure according to retrospective studies. A cross-sectional study involving 90 children reported that pre-hypertension and hypertension were independently associated with the presence of albuminuria. Prospective studies are needed to determine the causal relationship of these findings as well as the potential benefits of treatment on the development of albuminuria.

In a recent prospective study involving 300 adults aged 20-70 years, [75] the prevalence of albuminuria was 68% (26% proteinuria) in homozygous individuals versus 32% (10% proteinuria) in heterozygous patients; [76] in this latter study, 21% of the patients had renal failure. [77] However, increased tubular secretion of creatinine is maintained with the abnormal GFR. Albuminuria is a very sensitive marker for the glomerular damage caused in the SCD, unlike in other nephropathies such as type-2 diabetes. For this reason, some authors [32] have prefered measuring blood levels of cystatin C to serum creatinine for the estimation of GFR, although more studies are needed to confirm this recommendation.

Although proteinuria can reach nephrotic levels, it increases gradually with age and is associated with higher levels of anemia, hemolysis and reticulocytosis, [78] and has also been correlated with the incidence of painful crises, cholelithiasis, acute chest syndrome and stroke. This condition is more prevalent in patients with four intact α-globin genes and less prevalent among α-thalassemia patients, with a prevalence of 40% among the HbSS adults without α-thalassemia and only 13% in the HbSS adults with α-thalassemia. Additionally, the mean blood pressure is greater in the patients with four intact α-globin genes than in those with α-thalassemia. [79]

Four different types of glomerulopathies have been described in the SCD: Focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), glomerulopathy specific to the SCD and thrombotic microangiopathy (TMA). [80] Regardless of which type of glomerular damage is present, all renal biopsies from the SCD patients show hypertrophied glomeruli with distended capillaries due to the sickled blood cells, which is described as a glomerulopathy specific to the SCD. Hemosiderin deposits in the tubular cells are an almost universal finding. The most common glomerulopathy is FSGS, [5],[61] which was observed in 39% of 18 renal biopsies from patients with the SCD [Figure 5]. [80] Because this disease mainly affects juxtamedullary glomeruli vascularized by the vasa recta, it is frequently accompanied by severe medullary fibrosis. Both immunofluorescence and electron microscope analyses provide evidence of an absence of immune deposits. In a smaller percentage of cases, global glomerular sclerosis is observed. [5] There have also been cases of focal cortical infarcts.
Figure 5: Sickle cell nephropathy, focal segmental glomerulosclerosis (FSGS). The segmental sclerotic lesion is composed of obliteration of capillary lumens and glomerular collapse (Jones' silver stain, ×400.)

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The second most frequently observed type is MPGN, which was originally the first glomerular abnormality reported in SCD. Although it has been associated with nephropathy due to HCV and HIV, none of the five cases described in the study by Maigne et al [80] were attributable to this relationship. Indirect immunofluorescence studies can reveal immune deposits predominantly in the capillary wall including IgG, IgM, IgA, C3 and C1q. Interstitial fibrosis is found in most cases.

Finally, characteristic lesions from TMA are evident in 17% of the cases, accompanied by some level of interstitial fibrosis. [80]

   Pathogenesis Top

It is believed that the initial mechanism for the development of a glomerulopathy in this context is hyperfiltration or an increase in GFR, which is common in the SCD patients, especially children. [49] Additionally, renal plasma flow is elevated even more than GFR, such that the filtration fraction is reduced in the SCD patients as compared with the normal subjects. [32] One explanation for this finding maybe that increased cortical plasma flow caused by the vasodilatory effect of prostaglandins could reduce the efficacy of diffusion due to the increased velocity (inhibition of prostaglandins re-establishes normal renal plasma flow and filtration fraction). However, hyperfiltration in the SCD is not only associated with hemodynamic changes but the glomerular permeability and the glomerular filtration coefficient are also increased. [81] The increased transglomerular traffic of macromolecules associated with the defects in the podocyte barrier due to glomerular hypertrophy could be the cause of the SCD-associated glomerulosclerosis [81] in a similar manner as in non-insulin-dependent diabetes mellitus. [82]

The glomerular hypertrophy consistently found in the SCD could be at least in part secondary to chronic anemia (concordant with a lower prevalence of renal damage in the patients with the other types of less-anemic SCD, such as the HbSC). However, proteinuria in the SCD is neither universal nor is it related to the number or severity of crises, indicating that other factors are involved.

Hyperfiltration, glomerular hypertrophy and FSGS are not necessarily sequential or causal. Some common mechanism may act in all the three conditions, such as growth factors or inflammatory cytokines. FSGS may be the cause and not the consequence of interstitial fibrosis. This could obstruct efferent arterioles thus increasing intraglomerular pressure and resulting in glomerular sclerosis [Table 2].
Table 2: Factors that may induce focal segmental glomerulosclerosis in sickle cell disease.

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Other genes may be involved in the development of CKD in patients with SCD. Recently, the haplotype of gene MYH9 was proven to be associated with CKD due to its involvement in podocyte malfunction due to defects in the structure of myosin IIA. [83] This gene is very common (≥60%) in African Americans and in people from Sub-Saharan Africa, populations in which SCD is also particularly common. Currently, insufficient evidence exists in the medical literature regarding the role of MYH9 mutations as modifiers of the phenotypic expression of SCD. In a recently published study regarding genetic modulators of the severity of SCD involving 1265 patients from the Cooperative Study of Sickle Cell Disease, the MYH9 gene was not mentioned. [84]

   Diagnosis Top

The patients with SCD must be considered at-risk for CKD and should have regular (at least once per year) measurements of the urinary albumin to creatinine ratio (UACR) for early detection in children after 7 years of age, particularly in the severe cases of SCD.

The first urine in the morning is recommended for laboratory analyses. In cases of positive UACR, a second measurement is required for confirmation. The criteria for positive albuminuria (UACR >30 mg/g) and proteinuria (UACR >300 mg/g) are those used for CKD. [73]

When patients test positive for albuminuria, we recommend measuring blood levels of cystatin C or using isotope analyses ( 99 Tm-DTPA, 125 I-iothalamate) for estimating GFR. The formulas recommended by the international guidelines for CKD screening programs in the SCD patients may not be useful unless there is a significantly altered GFR (<35-40 mL/min/1.73 m 2 ).

Seropositivity must be tested for hepatitis virus and HIV due to the elevated prevalence of these diseases in SCD patients and their association with glomerulopathies.

A kidney biopsy must be considered in cases of rapid-onset nephrotic syndrome or rapidly progressing kidney disease.

   Acute Kidney Injury Top

There are a number of potential etiologies for acute kidney injury (AKI) among patients with SCD [Table 3]. As a result of impaired concentrating ability, they are pre-disposed to pre-renal failure secondary to intravascular volume depletion. Intrinsic renal causes of AKI include rhabdomyolysis, sepsis, drug nephroto-xicity, renal vein thrombosis and even hepatorenal syndrome (hemosiderosis-induced hepatic failure). Post-renal causes include urinary tract obstruction secondary to blood clots and, less commonly, papillary necrosis. The prognosis appears to be favorable, with one small study reporting a rate of recovery of 83%. [85]
Table 3: Diagnostic and therapeutic approach to patients with SCN.

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In one study, the incidence of AKI during vaso-occlusive crises was surprisingly low (<5%) and appeared to be limited to those with acute coronary syndrome and pulmonary hypertension, suggesting a potential role for right ventricular dysfunction and venous congestion. [96] However, a higher incidence of AKI (10%) was reported in another study of hospitalized patients with SCD. [85] Such a wide variation in results could probably be due to the differing criteria used to define AKI and its timing of onset.

   Chronic Renal Failure in Sickle Cell Disease Top

The possibility that proteinuria may accelerate kidney disease progression to end-stage renal failure has received support from the results of increasing numbers of experimental and clinical studies. [87] Baseline proteinuria was an independent predictor of renal outcome in patients with diabetes, non-diabetes as well as SCNs. [88],[89],[90] Clinical trials consistently showed renoprotective effects of proteinuric reduction and led to the recognition that the anti-proteinuric treatment is instrumental to maximize renoprotection. [88],[91],[92],[93]

In addition to the nephropathy associated with SCD, it is also possible that the medullary ischemia induced by sickling can exacerbate the course of the other underlying renal diseases. There is, for example, some evidence that black patients with a sickle cell trait and autosomal dominant polycystic kidney disease develop ESRD earlier than those without sickle hemoglobin. [94]

   Therapeutic Aspects Top

Management of proteinuria

The evolution of patients with albuminuria should be monitored, and at least those patients with proteinuria should be treated, due to the increased probability of renal function deterioration. The SCD as well as other proteinuric glomerulopathies are probably modifiable using measures to halt its progression, such as renin-angiotensin-aldosterone system inhibitors. More evidence has been compiled for angiotensin converting enzyme (ACE) inhibitors, which have been shown to reduce proteinuria in adults and children with SCD. [5],[41] The use of these drugs implies a greater risk of hyperkalemia in patients with SCD due to hemolysis, making preventive measures especially necessary, along with monitoring potassium levels and even suspending treatment during hemolytic crises. [5]

Transfusions or HU may have some protective value, especially because of the importance of anemia and hemolysis as risk factors for kidney disease. Treatment with HU has been shown to prevent the development of proteinuria in children and even decrease the rate of albuminuria. [41] This drug improves anemia and erythrocyte rheology, reduces leukocytosis and modulates the expression of adhesion molecules. The combined use of ACE inhibitors and HU can prevent the progression of microalbuminuria to proteinuria, [95] although its effect in preventing renal failure has not been evaluated.

Steinberg et al [96] recently published their results from a long-term follow-up of 299 patients included in the Multicenter Study of HU in sickle cell anemia spanning 17.5 years. These authors observed a global prevalence of CKD of 17.4%, 19% in patients who received HU during a cumulative period less than 5 years and 5% in patients treated with HU for 15 years or more. The safety of this drug and the reduced mortality observed in patients receiving long-term HU treatment suggest that CKD could become one of the expanded criteria indicated for HU treatment in the SCD patients without frequent vaso-occlusive events. [96]

Management of tubular dysfunction

It is not usually necessary to treat tubular dysfunction. Preventive measures such as encouraging patients to increase fluid ingestion in situations of greater water loss can be used to avoid complications. Diarrhea and dehydration should be treated promptly, keeping in mind that these patients have a lower ability to concentrate urine and, hence, become dehydrated more easily. Because tubular sodium re-absorption is increased, possibly causing cardiac insufficiency, physicians must avoid prescribing large volumes with standard sodium content for water repletion in these patients. [97] Hyperuricemia can be aggravated by the use of diuretics, particularly thiazides. During hemolytic crises, the physician should be alert to the increase in serum potassium. In these cases, the use of β-blockers or ACE inhibitors can aggravate hyperkalemia. A β-stimulant, on the other hand, may be important to move this ion into the cells. [97] Besides reducing ammonia excretion, [98] indomethacin decreases GFR and effective renal plasma flow significantly, and it is therefore not recommended in Hb-SS patients. [32],[53]

Management of hematuria and RPN

Because the pathology of sickle cell hematuria is generally benign and self-limiting, a conservative treatment with bed rest is appropriate for avoiding the detachment of microthrombi. Forced diuresis should be maintained (at 4l/1.73 m 2 per day) using hydration, preferably with hypotonic solutions, along with administration of thiazide or loop diuretics. This will reduce medullary osmolality and may reduce cell sickling in the vasa recta as well as aid in eliminating clots in the urinary tract. Volume expansion with saline solution must be avoided as this would be ineffective at reducing blood osmolality, and transfusions can increase the risk of heart failure.

Combined treatment with vasopressin is defended by some authors as this would induce hydration of the erythrocytes, decreasing the concentration of HbSS and thus the rate of cell sickling. [99]

Alkalization is also recommended as this is potentially useful for increasing the affinity of hemoglobin (Hb) for O 2 and decreasing the rate of cell sickling as well as the tubular toxicity of hemoglobinuria. However, this approach has not been proven as an effective treatment method.

The use of -aminocaproic acid is reserved for those cases in which previous treatment methods have failed, and this method requires a great deal of precaution due to the high risk of thrombosis.

In isolated cases of severe hematuria that has not responded to the previously mentioned treatment options, arteriography localization and selective embolization of the affected renal segment may ensue in order to prevent a nephrectomy.

In any case, the treatment of hematuria must be included within the general treatment of SCD, especially the use of HU, which has been proven effective in both adults and children at reducing the incidence of crises with an acceptable safety profile. [100] The use of anti-oxidant agents such as ascorbic acid could protect kidney cells from the oxidative damage of HU and increase safety.


The incidence of hemodialysis-related complications does not appear to be different in the SCD patients when compared with the general dialysis population, although survival appears to be diminished. [101] In a study using data from the United States Renal Data System (USRDS), of the 397 incident dialysis SCD patients, the 2-year mortality was similar to that of patients without SCD (33% and 37%, respectively). [102] However, the SCD patients were substantially younger at the initiation of dialysis (mean age 40 versus 60 years). In the same study, an age-matched analysis of patients with a mean age of 35 years demonstrated a greater difference in survival (60 versus 80% at 3 years and 40 versus 70% at 5 years for patients with and without SCN, respectively).

Kidney transplantation

The SCD patients have a relative erythropoietin deficiency. Steinberg described good results when the SCD patients who had chronic renal failure used higher doses of epoetin-α than those with other forms of ESRD. [103] However, the results obtained by Roger et al with this drug in similar situations were disappointing. [104] Bone marrow transplantation has recently emerged as a novel treatment for SCD. As this procedure is associated with a high morbidity and mortality, it has been indicated in a relatively small number of patients. [105] Whether bone marrow transplantation can stop the progression of SCN is unknown. [2] Renal transplantation, on the other hand, can be an effective treatment for the SCD patients, allowing an improvement in anemia and quality of life. The role of renal transplantation as a treatment for the end-stage SCN has not been well established. It is possible that physicians do not offer treatment to many SCN patients with CKD, assuming a poor chance for successful therapy. Ojo and colleagues [106] reported that the short-term survival of renal allografts in recipients with end-stage SCN was similar to that achieved in patients with other causes of ESRD, but the long-term outcome was comparatively diminished. Furthermore, there was a trend toward better patient survival with renal transplantation compared with dialysis in end-stage SCN. Similar results hold true for adolescent patients. [107] Data from the national registry of renal allografts in the SCN recipients show a 1-year graft survival rate of 82% in living-related donor recipients and 62% in deceased donor kidney recipients. [108]

Adequate preparation of the patients before surgery consists of transfusions of lymphocyte-depleted packed cells (often required due to inherent erythropoietin resistance), with the caution that a rise in the hematocrit and the plasma viscosity may precipitate a plasma cell crisis, which is especially so in the first year after transplantation. The concurrent use of HU to increase hemoglobin F production, while decreasing the hematocrit, may reduce the frequency of the crises. [109] Moreover, in the SCD patients with chronic renal failure, a high hemoglobin level may precipitate painful crises; consequently, the recommended HB should range from 6 to 9 g/dL. [110]

Pre-transplant erythropoietin resistance improves dramatically after transplantation as the allograft's endogenous erythropoietin raises the hematocrit to a greater degree than recombinant erythropoietin in the pre-transplant state. [111] The challenge of achieving an optimal post-transplant hematocrit requires balancing the prevention of anemia complications and symptoms (hematocrit too low) and the prevention of a crisis (hematocrit too high). Furthermore, recurrence of the SCN may occur in the transplanted organ. [112]

   Recurrent Renal Disease Top

The frequency with which recurrence occurs in the allograft is not well documented. Miner et al [112] reported a case of a patient who developed a permanent decline in renal function 3.5 years after transplant due to recurrence of SCN and Chaterjee et al [113] provided another early case report of post-transplant renal allograft dysfunction that was not reversible by immunosuppression and was related to intravascular sickling. O'Rourke et al [114] recently presented a radiographic teaching case in which recurrent sickle cell involvement of the allograft presented as acute dysfunction, with biopsy findings of vascular congestion and patchy cortical necrosis.

Because of the numerous transfusions such patients often receive prior to transplantation, the presence of pre-formed antibodies may pose a problem with regard to the donor organ and, thus, risk of rejection.

Close monitoring of fluid intake and output should be performed post-transplantation. Fluid deprivation, excessive fluid loss and inability to ingest fluids can induce dehydration in the SCD patients more rapidly than in the normal population thus exposing the patient to the additional risk of a potential sickle cell crisis.

Finally, some of the SCN patients undergo a splenectomy as part of their therapy. [115] As such patients are at risk of infection with encapsulated organisms such as Pneumococci, pneumococcal vaccination is safe and effective in patients with well-functioning renal allografts, at least in the short term. This vaccination policy may be useful for preventing post-transplant invasive pneumococcal disease in the SCN patients. [116]

   References Top

1.Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-44.  Back to cited text no. 1
2.Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int 2000;57:1-8.  Back to cited text no. 2
3.MogensenCE, Hansen KW, Nielsen S, Pedersen MM, Rehling M, Schmitz A. Monitoring diabetic nephropathy: Glomerular filtration rate and abnormal albuminuria in diabetic renal disease: Reproducibility, progression, and efficacy of antihypertensive intervention. Am J Kidney Dis 1993;22:174-87.  Back to cited text no. 3
4.Thomas AN, Pattison C, Serjeant GR. Causes of death in sickle-cell disease in Jamaica. BMJ 1982;285:633-5.  Back to cited text no. 4
5.Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 1992;326:910-5.  Back to cited text no. 5
6.Aoki RY, Saad ST. Enalapril reduces the albuminuria of patients with sickle cell disease. Am J Med 1995;98:432-5.  Back to cited text no. 6
7.Serjeant GR, Serjeant BE, Forbes M, Hayes RJ, Higgs DR, Lehmann H. Hemoglobin gene frequencies in the Jamaican population: A study in 100,000 newborns. Br J Haematol 1986;64:253-62.  Back to cited text no. 7
8.Scheinman JL. Sickle cell nephropathy. In: Barret TM, Avner ED, Armon WE, eds. Pediatric Nephrology, 4 th ed. Baltimore: Lippincott, Williams and Wilkins; 1999. p. 497-507.  Back to cited text no. 8
9.Statius van Eps LW, Pinedo-Veels C, de Vries GH, de Koning J. Nature of concentrating defect in sickle-cell nephropathy. Microradioangiographic studies. Lancet 1970;1:450-2.  Back to cited text no. 9
10.McInnes BK 3rd. The management of hematuria associated with sickle hemoglobinopathies. J Urol 1980;124:171-4.  Back to cited text no. 10
11.Mostofi FK, Vorder Bruegge CF, Diggs LW. Lesions in kidneys removed for unilateral hematuria in sickle cell disease. AMA Arch Pathol 1957;63:336-51.  Back to cited text no. 11
12.Osegbe DN. Haematuria and sickle cell disease. A report of 12 cases and review of the literature. Trop Geogr Med 1990;42:22-7.  Back to cited text no. 12
13.Khan A, Thomas N, Costello B, et al. Renal medullary carcinoma: Sonographic, computed tomography, magnetic resonance and angiographic findings. Eur J Radiol 2000;35:1-7.  Back to cited text no. 13
14.Wesche WA, Wilimas J, Khare V, Parham DM. Renal medullary carcinoma: A potential sickle cell nephropathy of children and adolescents. Pediatr Pathol Lab Med 1998;18:97-113.  Back to cited text no. 14
15.Allen TD. Sickle cell disease and hematuria: Report of 29 cases. J Urol 1964;91:177-83.  Back to cited text no. 15
16.Bennett MA, Heslop RW, Meynell MJ. Massive hematuria associated with sickle-cell trait. Br Med J 1967;1:677-9.  Back to cited text no. 16
17.Chapman AZ, Reeder PS, Friedman IA, Baker LA. Gross hematuria in sickle cell trait and sickle cell hemoglobin-C disease. Am J Med 1955;19:773-82.  Back to cited text no. 17
18.Turner JD, Milhorn HT Jr. Gross hematuria in a patient with sickle cell trait. Postgrad Med 1985;78:151-4.  Back to cited text no. 18
19.Goodwin WE, Alston EF, Semans JH. Hematuria and sickle cell disease: Unexplained gross unilateral hematuria in Negros, coincident with the blood sickling trait. J Urol 1950;63:79-82.  Back to cited text no. 19
20.Buckalew VM Jr, Someren A. Renal manifestations of sickle cell disease. Arch Intern Med 1974;133:660-9.  Back to cited text no. 20
21.Marynick SP, Ramsey EJ, Knochel JP. The effect of bicarbonate and distilled water on sickle cell trait hematuria and in vitrostudies on the interaction of osmolality and pH on erythrocyte sickling in sickle cell trait. J Urol 1977;118:793-6.  Back to cited text no. 21
22.Odita JC, Ugbodaga CI, Okafor LA, Ojogwu LI, Ogisi OA. Urographic changes in homozygous sickle cell disease. Diagn Imaging 1983;52:259-63.  Back to cited text no. 22
23.Falk RJ, Jennette JC. Sickle cell nephropathy. Adv Nephrol Necker Hosp 1994;23:133-47.  Back to cited text no. 23
24.Pandya KK, Koshy M, Brown N, Presman D. Renal papillary necrosis in sickle cell hemoglobinopathies. J Urol 1976;115:497-501.  Back to cited text no. 24
25.Nagel RL. Sickle cell anemia is a multi-gene disease: Sickle painful crises, a case in point. Am J Hematol 1993;42:96-101.  Back to cited text no. 25
26.Kaul DK, Fabry ME, Nagel RL. The pathophysiology of vascular obstruction in the sickle syndromes. Blood Rev 1996;10:29-44.  Back to cited text no. 26
27.Nagel RL, Bookchin RM, Johnson J, et al. Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. Proc Natl Acad Sci USA 1979;76:670-72.  Back to cited text no. 27
28.Chang YP, Maier-Redelsperger M, Smith KD, et al. The relative importance of the X linked FCP locus and beta-globin haplotypes in determining haemoglobin F levels: A study of SS patients homozygous forbeta S haplotypes. Br J Haematol 1997;96:806-14.  Back to cited text no. 28
29.López Revuelta K, Ricard Andrés MP. Kidney abnormalities in sickle cell disease. Nefrologia 2011;31:591-601.  Back to cited text no. 29
30.Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia. Radiographics 2001;21: 971-94.  Back to cited text no. 30
31.McCall IW, Moule N, Desai P, Serjeant GR. Urographic findingsin homozygous sickle cell disease. Radiology 1978;126:99-104.  Back to cited text no. 31
32.Allon M, Lawson L, Eckman JR, Delaney V, Bourke E. Effects of non steroidal anti-inflammatory drugs on renal function in sickle cell anemia. Kidney Int 1988;34:500-6.  Back to cited text no. 32
33.Alvarez O, Lopez-Mitnik G, Zilleruelo G. Short-term follow-up of patients with sickle cell disease and albuminuria. Pediatr Blood Cancer 2008;50:1236-9.  Back to cited text no. 33
34.Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: Risk factors, clinical course, and mortality. Ann Intern Med 1991;115:614-20.  Back to cited text no. 34
35.Diamond HS, Meisel A, Sharon E, Holden D, Cacatian A. Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia. Am J Med 1975;59:796-802.  Back to cited text no. 35
36.Diamond HS, Meisel AD, Holden D. The natural history of urate overproduction in sickle cell anemia. Ann Intern Med 1979;90: 752-7.  Back to cited text no. 36
37.Walker BR, Alexander F. Uric acid secretion in sickle cell anemia. JAMA 1971;215:255-8.  Back to cited text no. 37
38.De Jong PE, de Jong-van Den Berg LT, Statius van Eps LW. The tubular reabsorption of phosphate in sickle-cell nephropathy. Clin Sci Mol Med 1978;55:429-34.  Back to cited text no. 38
39.Smith EC, Valika KS, Woo JE, O'Donnell JG, Gordon DL, Westerman MP. Serum phosphate abnormalities in sickle cell anemia. Proc Soc Exp Biol Med 1981;168:254-88.  Back to cited text no. 39
40.Barreras L, Diggs LW, Lipscomb A. Plasma volume in sickle cell disease. South Med J 1966;59:456-8.  Back to cited text no. 40
41.Hatch FE, Crowe LR, Miles DE, Young JP, Portner ME. Altered vascular reactivity in sickle hemoglobinopathy. A possible protective factor from hypertension. Am J Hypertens 1989;2:2-8.  Back to cited text no. 41
42.Wilson WA, Alleyne GA. Total body water, extracellular and plasma volume compartments in sickle cell anemia. West Indian Med J 1976; 25:241-50.  Back to cited text no. 42
43.de Jong PE, de Jong-van den Berg LT, Sewrajsingh GS, Schouten H, Donker AJ, Statius van Eps LW. Beta-2 microglobulin in sickle cell anaemia. Evidence of increased tubular reabsorption. Nephron 1981;29:138-41.  Back to cited text no. 43
44.Miller ST, Wang WC, Iyer R, et al. Urine concentrating ability in infants with sickle cell disease: Baseline data from the phase III trial of hydroxyurea (BABY HUG). Pediatr Blood Cancer. 2010;54:265-8.  Back to cited text no. 44
45.Scheinman JI. Pediatric Nephrology. In: Holliday M, Barratt TM, Avner D, eds. Sickle cell nephropathy. Baltimore: Williams and Wilkins; 1994. p. 908.  Back to cited text no. 45
46.Saborio P, Scheinman JI. Disease of the month - Sickle cell nephropathy. J Am Soc Nephrol 1999;10:187-92.  Back to cited text no. 46
47.Bayazit AK, Noyan A, Aldudak B, et al. Renal function in children with sickle cell anemia. Clin Nephrol 2002;57:127-30.  Back to cited text no. 47
48.Batlle D, Itsarayoungyuen K, Arruda JA, Kurtzman NA. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Am J Med 1982;72:188-92.  Back to cited text no. 48
49.de Jong PE, Statius van Eps LW. Sickle cell nephropathy: New insights into its pathophysiology. Kidney Int 1985;27:711-7.  Back to cited text no. 49
50.Allon M. Renal abnormalities in sickle cell disease. Arch Intern Med 1990;150:501-4.  Back to cited text no. 50
51.Bruno D, Wigfall DR, Zimmerman SA, Rosoff PM, Wiener JS. Genitourinary complications of sickle cell disease. J Urol 2001;166:803-11.  Back to cited text no. 51
52.terMaaten JC, Serné EH, Bakker SJ, van Eps WS, Donker AJ, Gans RO. Effects of insulin on glucose uptake and leg blood flow in patients with sickle cell disease and normal subjects. Metabolism 2001;50:387-92.  Back to cited text no. 52
53.de Jong PE, de Jong-Van Den Berg TW, Sewrajsingh GS, Schouten H, Donker AJ, Statius van Eps LW. The influence of indome-thacin on renal haemodynamics in sickle cell anaemia. Clin Sci (Lond) 1980;59:245-50.  Back to cited text no. 53
54.Etteldorf JN, Tuttle AH, Clayton GW. Renal function studies in pediatrics. Am J Dis Child 1952;83:185-91.  Back to cited text no. 54
55.Statius van Eps LW, Schouten H, La Porte-Wijsman LW, Struyker Boudier AM. The influence of red blood cell transfusions on the hyposthenuria and renal hemodynamics of sickle cell anemia. Clin Chim Acta 1967;17: 449-61.  Back to cited text no. 55
56.Bank N, Aynedjian HS, Qiu JH, et al. Renal nitric oxide synthases in transgenic sickle cell mice. Kidney Int 1996;50:184-9.  Back to cited text no. 56
57.Bank N, Kiroycheva M, Ahmed F, et al. Peroxynitrite formation and apoptosis in transgenic sickle cell mouse kidneys. Kidney Int 1998;54:1520-8.  Back to cited text no. 57
58.Etteldorf JN, Smith JD, Tuttle AH, Diggs LW. Renal hemodynamic studies in adults with sickle cell anemia. Am J Med 1955;18:243-8.  Back to cited text no. 58
59.Morgan AG, Serjeant GR. Renal function in patients over 40 with homozygous sickle-cell disease. Br Med J (Clin Res Ed) 1981;282:1181-3.  Back to cited text no. 59
60.Alleyne GA. The kidney in sickle cell anemia. Kidney Int 1975;7:371-9.  Back to cited text no. 60
61.Bhathena DB, Sondheimer JH. The glomerulopathy of homozygous sickle hemoglobin (SS) disease: Morphology and pathogenesis. J Am Soc Nephrol 1991;1:1241-52.  Back to cited text no. 61
62.Statius van Eps LW, Schouten H, Haar Romeny-Wachter CC, La Porte-Wijsman LW. The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease. Clin Chim Acta 1970; 27:501-5.  Back to cited text no. 62
63.Hakimi AA, Koi PT, Mihoua PM, et al. Renal medullary carcinoma: The Bronx experience. Urology 2007;70:878-82.  Back to cited text no. 63
64.Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol 1995;19:1-11.  Back to cited text no. 64
65.Swartz MA, Karth J, Schneider DT, Rodriguez R, Beckwith JB, Perlman EJ. Renal medullary carcinoma: Clinical, pathologic, immunohistochemical and genetic analysis with pathogenetic implications. Urology 2002;60:1083-9.  Back to cited text no. 65
66.Avery RA, Harris JE, Davis CJ Jr, Borgaonkar DS, Byrd JC, Weiss RB. Renal medullary carcinoma: Clinical and therapeutic aspects of a newly described tumor. Cancer 1996;78:128-32.  Back to cited text no. 66
67.Strouse JJ, Spervak M, Mack AK, Arceci RJ, Small D, Loeb DM. Significant responses to platinum-based chemotherapy in renal medullary carcinoma. Pediatr Blood Caner 2005;44: 407-11.  Back to cited text no. 67
68.Schultz WH, Ware RE. Malignancy in patients with sickle cell disease. Am J Hematol 2003;74:249-53.  Back to cited text no. 68
69.Lowe LH, Isuani BH, Heller RM, et al. Pediatric renal masses: Wilms tumor and beyond. Radiographics 2000;20:1585-603.  Back to cited text no. 69
70.Halsey C, Roberts IA. The role of hydroxyurea in sickle cell disease. Br J Hematol 2003; 120:177-86.  Back to cited text no. 70
71.Najean Y, Rain JD. Treatment of polycythemia Vera: Use of 32P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. The French Polycythemia Study Group. Blood 1997;89:2319-27.  Back to cited text no. 71
72.Álvarez O, López-Mitnik G, Zilleruelo G. Short-term follow-up of patients with sickle cell disease and albuminuria. Pediatr Blood Cancer 2008;50:12363-9.  Back to cited text no. 72
73.McKie KT, Hanevold CD, Hernandez C, Waller JL, Ortiz L, McKie KM. Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease. J Pediatr Hematol Oncol 2007;29:140-4.  Back to cited text no. 73
74.Becton LJ, Kalpatthi RV, Rackoff E, et al. Prevalence and clinical correlates of microalbuminuria in children with sickle cell disease. Pediatr Nephrol 2010;25:1505-11.  Back to cited text no. 74
75.Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 2006;17:2228-35.  Back to cited text no. 75
76.K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39 (2 Suppl 1):S1-266.  Back to cited text no. 76
77.Guasch A, Cua M, Mitch WE. Extent and the course of glomerular injury in patients with sickle cell anemia. Kidney Int 1996;49:786-91.  Back to cited text no. 77
78.Zayas CF, Platt J, Eckman JR, et al. Prevalence and predictors of glomerular involvement in sicklecell anemia. J Am Soc Nephrol 1996; 7:1401.  Back to cited text no. 78
79.Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subfenotypes. Blood Rev 2007;21:37-47.  Back to cited text no. 79
80.Maigne G, Ferlicot S, Galacteros F, et al. Glomerular lesions in patients with sickle cell disease. Medicine 2010;89:18-27.  Back to cited text no. 80
81.Schmitt F, Martinez F, Brillet G, et al. Early glomerular dysfunction in patients with sickle cell anemia. Am J Kidney Dis 1998;32:208-14.  Back to cited text no. 81
82.Scandling JD, Myers BD. Glomerular size-selectivity and microalbuminuria in early diabetic glomerular disease. Kidney Int 1992; 41:840-6.  Back to cited text no. 82
83.Oleksyk TK, Nelson GW, An P, Kopp JB, Winkler CA. Worldwide distribution of the MYH9 kidney disease susceptibility alleles and haplotypes: Evidence of historical selection in Africa. PloS One 2010;5:e11474.  Back to cited text no. 83
84.Sebastiani P, Solovieff N, Hartley SW, et al. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol 2010;85:29-35.  Back to cited text no. 84
85.Sklar AH, Perez JC, Harp RJ, Caruana RJ. Acute renal failure in sickle cell anemia. Int J Artif Organs 1990;13:347-51.  Back to cited text no. 85
86.Audard V, Homs S, Habibi A, et al. Acute kidney injury in sickle patients with painful crisis or acute chest syndrome and its relation to pulmonary hypertension. Nephrol Dial Transplant 2010;25:2524-9.  Back to cited text no. 86
87.Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive Renal Damage? J Am Soc Nephrol 2006;17:2974-84.  Back to cited text no. 87
88.Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progress-sion of renal disease. The Modification of diet in renal disease study. Ann Intern Med 1995; 123:754-62.  Back to cited text no. 88
89.Breyer JA, Bain RP, Evans JK, et al. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. The Collaborative study Group. Kidney Int 1996;50:1651-8.  Back to cited text no. 89
90.Abdu A, Emokpae MA, Uadia PO, Kuliya-Gwarzo A. Proteinuria among adult sickle cell anaemia patients in Nigeria. Ann Afr Med 2011;10:34-7.  Back to cited text no. 90
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91.Wapstra FH, Navis G, de Jong PE, de Zeeuw D. Prognostic value of the short-term antiproteinuric response to ACE inhibition for prediction of GFR decline in patients with non diabetic renal disease. Nephrol 1996;4 Suppl 1:47-52.  Back to cited text no. 91
92.Ruggenenti P, Perna A, Remuzzi G. Retarding progression of chronic renal disease; the neglected issue of residual proteinuria. Kidney Int 2003;63:2254-61.  Back to cited text no. 92
93.Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl Med 2001;345:861-9.  Back to cited text no. 93
94.Yium J, Gabow P, Johnson A, Kimberling W, Martinez-Maldonado M. Autosomal dominant polycystic kidney disease in blacks: Clinical course and effects of sickle-cell hemoglobin. J Am Soc Nephrol 1994;4:1670-4.  Back to cited text no. 94
95.Fitzhugh CD, Wigfall DR, Ware RE. Enalapril and hydroxyurea therapy for children with sickle nephropathy. Pediatr Blood Cancer 2005;45:982-5.  Back to cited text no. 95
96.Steinberg MH, McCarthy WF, Castro O, et al, and investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients Follow up. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010;85:403-8.  Back to cited text no. 96
97.de Santis Feltran L, de Abreu Carvalhaes JT, Sesso R. Renal complications of sickle cell disease: Managing for optimal outcomes. Paediatr Drugs 2002;4:29-36.  Back to cited text no. 97
98.de Jong PE, de Jong-van den Berg LT, Schouten H, Donker AJ, Statius van Eps LW. The influence of indomethacin on renal acidification in normal subjects and in patients with sickle cell anemia. Clin Nephrol 1983;19:259-64.  Back to cited text no. 98
99.Van Eps S, De Jong PE. Sickle cell disease. In Schrier RW, Gottschalk CW, eds. Boston: Little, Brown and Company; 1988. p. 2561-81.  Back to cited text no. 99
100.Brawley OW, Cornelius LJ, Edwards LR, et al. National Institutes of Health consensus development conference statement: Hydroxyurea treatment for sickle cell disease. Ann Intern Med 2008;148:932-8.  Back to cited text no. 100
101.Wong WY, Elliott-Mills D, Powars D. Renal failure in sickle cell anemia. Hematol Oncol Clin North Am 1996;10:1321-31.  Back to cited text no. 101
102.Abbott KC, Hypolite IO, Agodoa LY. Sickle cell nephropathy at end-stage renal disease in the United States: Patient characteristics and survival. Clin Nephrol 2002;58:9-15.  Back to cited text no. 102
103.Steinberg MH. Erythropoietin for anemia of renal failure in sickle cell disease. N Engl J Med 1991;324:1369-70.  Back to cited text no. 103
104.Roger SD, Macdougall IC, Thuraisingham RC, Raine AE. Erythropoietin in anemia of renal failure in sickle cell disease. N Engl J Med 1991;325:1175-6.  Back to cited text no. 104
105.Kirkpatrick DV, Barrios NJ, Humbert JH. Bone marrow transplantation for sickle cell anemia. Semin Hematol 1991;28:240-3.  Back to cited text no. 105
106.Ojo AO, Govaerts TC, Schmouder RL, Leicht-man AB. Renal transplantation in end-stage sickle cell nephropathy. Transplantation 1999; 67:291-5.  Back to cited text no. 106
107.Warady BA, Sullivan EK. Renal transplantation in children with sickle cell disease: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1998;2:130-3.  Back to cited text no. 107
108.Chatterjee SN. National Study in natural history of renal allografts in sickle cell disease or trait: A second report. Transplant Proc 1987;19(2 Suppl 2):33-5.  Back to cited text no. 108
109.Allen A, Scoble J, Snowden S, Hambley H, Bellingham A. Hydroxyurea, sickle cell disease and renal transplantation. Nephron 1997; 75:106-7.  Back to cited text no. 109
110.van Ypersele de Strihou C. Should anaemia in subtypes of CRF patients be managed differrently? Nephrol Dial Transplant 1999;14 Suppl 2:37-45.  Back to cited text no. 110
111.Breen CP, Macdougall IC. Improvement of erythropoietin-resistant anaemia after renal transplantation in patients with homozygous sickle-cell disease. Nephrol Dial Transplant 1998;13:2949-52.  Back to cited text no. 111
112.Miner DJ, Jorkasky DK, Perloff LJ, Grossman RA, Tomaszewski JE. Recurrent sickle cell nephropathy in a transplanted kidney. Am J Kidney Dis 1987;10:306-13.  Back to cited text no. 112
113.Chatterjee SN, Lundberg GD, Berne TV. Sickle cell trait: Possible contributory cause of renal allograft failure. Urology 1978;11:266-8.  Back to cited text no. 113
114.O'Rourke EJ, Laing CM, Khan AU, et al. The case. Allograft dysfunction in a patient with sickle cell disease. Kidney Int 2008;74:1219-20.  Back to cited text no. 114
115.Kar BC. Splenectomy in sickle cell disease. J Assoc Physicians India 1999;47:890-3.  Back to cited text no. 115
116.Kazancioglu R, Sever MS, Yuksel-Onel D. Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine. Clin Transplant 2000;14:61-5.  Back to cited text no. 116

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King Fahad University Hospital, Dammam University, Al Khobar
Kingdom of Saudi Arabia
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DOI: 10.4103/1319-2442.128495

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[Pubmed] | [DOI]
3 Sickle cell disease nephropathy: an update on risk factors and potential biomarkers in pediatric patients
André R Belisário, Ariadna AS da Silva, Cristiane VM Silva, Larissa MG de Souza, Eduarda A Wakabayashi, Stanley de A Araújo, Ana C Simoes-e-Silva
Biomarkers in Medicine. 2019; 13(11): 965
[Pubmed] | [DOI]


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