Saudi Journal of Kidney Diseases and Transplantation

REVIEW ARTICLE
Year
: 2014  |  Volume : 25  |  Issue : 2  |  Page : 249--265

An update on sickle cell nephropathy


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

Correspondence Address:
Abdullah Alhwiesh
King Fahad University Hospital, Dammam University, Al Khobar
Kingdom of Saudi Arabia

Abstract

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;25:249-265


How to cite this URL:
Alhwiesh A. An update on sickle cell nephropathy. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Dec 15 ];25:249-265
Available from: http://www.sjkdt.org/text.asp?2014/25/2/249/128495


Full Text

 Introduction



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}

 Pathophysiology



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



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}

 Renal Papillary Necrosis



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}{Figure 3}

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



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}

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



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



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



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



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}

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



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}

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



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



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}

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



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



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.

Dialysis

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



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]

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