Sickle cell disease effects on the kidney

INTRODUCTION — Sickle cell disease (SCD) refers to a group of related hemoglobinopathies in which the sickle hemoglobin mutation is co-inherited with another beta globin mutation (eg, HbSS, sickle-beta thalassemia, HbSC disease) leading to sickling and vaso-occlusion. (See "Overview of compound sickle cell syndromes".)

Kidney injury in SCD, referred to as sickle cell nephropathy (SCN), is a common, under-recognized complication. In addition, there are numerous other potential effects of SCD on the kidney and urinary tract.

This topic reviews the effects of SCD on the kidney and our approach to monitoring, prevention, and treatment. Separate topic reviews discuss the pathophysiology of vaso-occlusion, other clinical manifestations of SCD, and our overall approach to management.

●Pathophysiology – (See "Pathophysiology of sickle cell disease".)

●Clinical features – (See "Overview of the clinical manifestations of sickle cell disease".)

●Management – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care" and "Overview of the management and prognosis of sickle cell disease" and "Sickle cell disease in sub-Saharan Africa".)

Effects of sickle cell trait on the kidney are also discussed separately. (See "Sickle cell trait", section on 'Urologic and kidney disease'.)

SICKLE CELL NEPHROPATHY

Pathogenesis — SCD has several related effects on the kidney, collectively referred to as "sickle cell nephropathy" (SCN) or "sickle nephropathy"; kidney damage is multifactorial and often only becomes apparent retrospectively after the serum creatinine increases above the reference range [1-3].

The major site of kidney injury is the renal medulla, which is supplied by the vasa recta capillaries (figure 1). These capillaries create an environment that is especially conducive to sickling because it is relatively hypoxic as well as acidic and hypertonic [4].

Hypoxia, acidosis, and hypertonicity all increase sickling by promoting sickle hemoglobin polymerization via effects on hemoglobin structure; hypertonicity may also affect hemoglobin concentration within the cell.

Sickling in turn affects the vasculature in a number of ways, including increasing adhesion of red blood cells (RBCs) to the vascular wall; increasing inflammation; increasing vascular tone (ie, causing vasoconstriction, as free hemoglobin from hemolysis sequesters nitric oxide [NO]); and activating platelets and coagulation factors [2,5,6]. The role of simple obstruction of blood flow by sickled cells, previously thought to be the primary mechanism of vaso-occlusion, may contribute but does not occur in isolation. This subject is discussed in more detail separately. (See "Pathophysiology of sickle cell disease".)

These vascular effects can cause renal medullary ischemia and infarction, with gradual loss of glomerular and tubular function [7]. Sickling in the vasa recta is also thought to lead to the loss of deep juxtamedullary nephrons and reduced countercurrent exchange in the inner medulla, in turn leading to impairment of free water reabsorption and impaired urinary concentrating ability (hyposthenuria), a common finding that may contribute to volume depletion, nocturia, and polyuria [8-10]. (See 'Enuresis' below.)

In contrast, the superficial loops of Henle in the cortical nephrons are supplied by peritubular capillaries, which do not experience the same degree of acidification, hypoxia, and hypertonicity.

The progression of changes and clinical features that appear over time are discussed below. (See 'Progression to clinically apparent findings' below.)

Some of the observed abnormalities have led to their investigation as possible disease biomarkers [11]. However, none of these markers have been validated clinically and none are being used outside of clinical trials. Examples of markers under study include the following:

●Proteins that might suggest hypoxia, hemolysis, and/or increased reactive oxygen species (eg, hypoxia-inducible factor 1 [HIF-1]; urinary and/or plasma endothelin 1 [ET-1]; serum lactate dehydrogenase [LDH] or asymmetric dimethylarginine [ADMA]), hemoglobinuria, or the kidney Doppler sonography resistive index and pulsatility index [12-18].

●Mediators of inflammation or vascular changes (eg, urinary transforming growth factor [TGF]-beta 1; urinary kallikrein; quinolinic acid [QA]; soluble serum fms-like tyrosine kinase 1 [sFlt-1]; or the ratio of serum Fas to serum Fas ligand [sFas/sFasL]) [15,17,19-22].

●Factors related to kidney injury or renal clearance (eg, serum cystatin C; urinary kidney injury molecule [KIM-1], N-acetyl-beta-D-glucosaminidase [NAG], beta2-microglobulin, BMPR1B, non-muscle myosin heavy chain 9 [MYH9], apolipoprotein 1 [APOL1] and others) [11,23-28]. Polymorphisms of the HMOX1 gene, which encodes the heme-oxygenase-1 enzyme, are also likely to affect the frequency of kidney disease [4].

Progression to clinically apparent findings — The following progression of changes is typical:

●Early changes – In infancy and early childhood, there may be increased glomerular pressure leading to compensatory kidney hypertrophy, glomerular hyperfiltration, and impaired urinary concentrating ability; creatinine is usually within the reference range [29-31]. Glomerular hyperfiltration is typically defined as an estimated glomerular filtration rate (eGFR) above a threshold value (eg, >130 mL/min per 1.73 m² for women and >140 mL/min per 1.73 m² for men) [5].

These changes may also be present in young adults; in one study, approximately half of adults <40 years of age had evidence of hyperfiltration [5]. Glomerular hyperfiltration is usually transient, followed by a decline in GFR over the ensuing years, as illustrated in a case series and an animal model [32,33]. It is not known whether hyperfiltration predicts the later development of chronic kidney disease [5,34]. (See "Secondary factors and progression of chronic kidney disease", section on 'Intraglomerular hypertension and glomerular hypertrophy'.)

Later in childhood or early adulthood, microalbuminuria, hematuria, or both may develop. The predominant left-sided origin of the hematuria has been attributed to the greater length of the left renal vein and the "nutcracker phenomenon," in which compression of the left renal vein between the aorta and superior mesenteric artery leads to increased blood pressure in the vein [35].

Hyperfiltration, defined as eGFR >180 mL/min/1.73m², is common and occurs early in children with SCD [36]. Hyperfiltration typically precedes albuminuria [32]. In one study, baseline GFR measured quantitatively by technetium 99m-labeled diethylenetriaminepentaacetic acid (DTPA) plasma clearance was performed in 184 infants (mean age, 13 months) [37]. The average DTPA GFR was 125.2 mL/min/1.73m² (compared to a normal value of 91.5 mL/min/1.73m²). DTPA GFR was correlated with age, weight, height, and kidney volume, but not with hemoglobin. Data from a second study in children with SCD indicated that hydroxyurea at maximum tolerated dose is associated with a decrease in hyperfiltration in young children with SCD [36].

As would be expected, because hyperfiltration occurs in children <1 year of age, there is a high rate hyperfiltration among adults. In a series of 280 adults with SCD, the prevalence of hyperfiltration assessed by Modification of Diet in Renal Disease (MDRD)-estimated GFR was 51 percent [5]. Among adults with hyperfiltration, approximately half had hyperfiltration alone, whereas smaller numbers had associated microalbuminuria or macroalbuminuria (36 and 15 percent, respectively). In a subgroup of 48 patients who underwent GFR measurement using a radioactive tracer, the sensitivity of the estimated GFR for hyperfiltration was 94 percent, and the specificity was 63 percent.

For reasons that are unclear, proximal tubular function is also supranormal [38]. This may be manifested by hyperphosphatemia (due to increased phosphate reabsorption) and an elevated creatinine clearance (due to enhanced creatinine secretion) that does not reflect the true GFR [30,39,40]. (See 'Accurate estimation of kidney function' below.)

Also by an unclear mechanism, there may be impaired distal hydrogen and potassium secretion, leading to a partial distal renal tubular acidosis [30,39,41-43]. Proposed explanations include medullary blood flow disturbance and hypoxia leading to reduced hydrogen ion and electrochemical gradients along the collecting ducts. Consequences may include hyperkalemia, which is typically mild and only becomes clinically apparent if there is a complicating factor such as potassium or acid loading, intravascular volume depletion, or rhabdomyolysis. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

Kidney biopsy generally is not performed, but reports of pathology in the early stages have described glomerular enlargement, hemosiderin deposits, papillary necrosis, and cortical infarction [8,31].

●Later changes – In early adulthood, macroalbuminuria and reduced GFR may be seen; however, creatinine may remain within the reference range because of the increased creatinine clearance. In later adulthood, there is progressive reduction in GFR and in some cases development of end-stage kidney disease (EKRD), as glomerular hypertrophy can no longer compensate for vascular dropout (image 1). At this point, the serum creatinine will be increased.

Less commonly, membranoproliferative glomerulonephritis (MPGN) with mesangial expansion and basement membrane duplication may be seen, either as an isolated finding or in association with focal segmental glomerulosclerosis (FSGS) [44,45]. It has been proposed that this form of MPGN is caused by fragmented RBCs lodged in isolated capillary loops and phagocytosed by mesangial cells, stimulating expansion of the mesangium and new basement membrane deposition [8,46]. In contrast to immune complex- and complement-mediated MPGN, in SCD there are no immune complexes or electron-dense deposits.

Reports of pathology in later stages have described interstitial inflammation, edema, fibrosis, tubular atrophy, papillary infarcts, and progressive glomerulosclerosis [8,31,47]. Unlike analgesic nephropathy, in which vasa recta are often spared, in SCN there is destruction of the vasa recta and vascular congestion of the collecting ducts, inner medulla, and papillae [48]. There is progressive nephron damage and FSGS (perihilar [most common] or collapsing), and the vasa recta are almost completely lost in some older individuals [31,44,47-49]. (See "Focal segmental glomerulosclerosis: Pathogenesis".)

Other factors may contribute to renal injury at any stage, as discussed in more detail separately (see "Secondary factors and progression of chronic kidney disease"). The following may be especially relevant to individuals with SCD:

●Nephrotoxic medications – Individuals with SCD are likely to receive a number of potentially nephrotoxic agents. (See 'Avoiding medications that are toxic to the kidney' below.)

Dosing of these drugs may be inappropriately high in some instances such as when estimation of the GFR used to calculate drug dosing is inaccurate (see 'Accurate estimation of kidney function' below) or when high doses of nonsteroidal antiinflammatory drugs (NSAIDs) are used in an attempt to minimize opioid pain medications. (See "Clinical manifestations and diagnosis of analgesic nephropathy".)

●Hypertension – Endothelial dysfunction can also lead to hypertension, which independently increases the risk of kidney disease. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of goal blood pressure on progression of CKD'.)

As with other manifestations of SCD, the severity and age of onset of SCN is variable (figure 2) [50]. SCN appears to be more severe with more severe genotypes (homozygous HbSS and sickle-beta⁰ thalassemia) than with milder genotypes (HbSC disease or sickle-beta⁺ thalassemia) [6,51]. However, there is significant variability even among individuals with the same genotype. (See 'Prevalence' below.)

Features that correlate with the risk of progressive kidney injury include hemoglobin genotype, age, hypertension, albuminuria, and low hemoglobin F (HbF) levels [2-4,52,53]. In addition, variants in the APOL1 gene, which encodes apolipoprotein L1, are emerging as risk factors for kidney disease in individuals with SCD as well as African Americans without SCD [25,54-56]. (See 'Pathogenesis' above.)

Individuals with SCD who have kidney disease often have other characteristics of the "hemolysis phenotype," including pulmonary hypertension, systemic hypertension, central nervous system (CNS) injury, and severe anemia [2]. Genetic factors that attenuate this hemolysis phenotype, such as co-inheritance of alpha thalassemia or the sickle-beta⁰ haplotype, will likely lower the risk of chronic kidney disease.

Prevalence — SCN leading to chronic kidney disease (CKD) occurs in as many as one-fourth to one-third of adults with SCD. The prevalence is higher in HbSS and sickle-beta⁰ thalassemia, but individuals with HbSC disease also develop SCN at a relatively high rate.

●A 2016 analysis determined the rates of kidney disease in adults with SCD enrolled in one of several clinical studies (Treatment of Pulmonary Hypertension and SCD with Sildenafil Therapy [Walk-PHaSST], Cooperative Study of SCD [CSSCD], and Multicenter Study of Hydroxyurea in SCD [MSH]) [51]. Collectively, these trials included 1470 individuals with homozygous HbSS. The Walk-PHaSST trial was the most recent of these trials, conducted from 2007 to 2009, and it also included 127 individuals with HbSC disease. Key findings included the following:

•Age was inversely correlated with eGFR (average loss of approximately 1.7 to 1.8 mL/min/1.73 m² per year in HbSS; approximately 1.1 mL/min/1.73 m² per year in HbSC). By comparison, age-related decline in eGFR in individuals without SCD is approximately 0.5 mL/min/1.73 m² per year.

•Moderately increased albuminuria (formerly called "microalbuminuria") was seen in 44 percent of those with HbSS and 23 percent of those with HbSC; severely increased albuminuria (formerly called "macroalbuminuria") was seen in 20 percent (both genotypes).

●A 2016 Medicaid database review of 9481 individuals with SCD hospitalized during the period from 2007 to 2012 documented the presence of CKD in 0.1 percent of children, 5.0 percent of adults, and 15.9 percent of adults over the age 40 years [57]. CKD was seen in 68 percent of admissions with hypertension and 25 percent of admissions with heart failure. Over the course of the study, new CKD was seen in 6.7 percent (annual incidence, 1.3 percent), which was approximately two- to threefold higher than in a non-SCD control group. Various smaller series have reported estimates of CKD in the range of 21 to 29 percent of adults with SCD [52,53].

●A 25-year longitudinal study from 1991 involving 725 individuals with HbSS and 209 with HbSC reported CKD in 4.2 and 2.4 percent, respectively [48]. The median age at which CKD occurred was 23 years for HbSS and 50 years for HbSC disease.

Evaluation

Routine surveillance and early detection — The development of CKD can be insidious, and ongoing surveillance is standard of care and an essential component of management for all individuals with SCD [2,3]. This is part of a larger program of care that includes a number of other routine assessments and preventive interventions. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments' and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

While surveillance is essential, high-quality evidence is lacking to guide the optimal tests and intervals for testing. Typically, routine evaluations are initiated by age three to five years and no later than 10 years of age. Routine visits occur approximately two to three times per year for children and approximately four to six times per year for adults. We typically do the following at every visit:

●Assessment of blood pressure. (See 'Blood pressure abnormalities' below.)

●At least annually, we check a urinalysis with examination of the urinary sediment and a spot urine albumin-to-creatinine ratio [58].

•If the urine albumin-to-creatinine ratio is above 300 mg/g, a 24-hour urine collection for protein quantification should be performed; typically this is done by the consulting nephrologist. We often repeat the urine albumin-to-creatinine ratio before referral to nephrology, in order to limit unnecessary referrals. Treatment of proteinuria is discussed below. (See 'Nephrologist referral and CKD interventions' below.)

•If microscopic hematuria is present, it is evaluated as discussed below. (See 'Evaluation of hematuria and flank pain' below.)

●A metabolic panel including serum creatinine, which is used to calculate the eGFR. Some experts recommend using the Schwartz formula, and others use other formulas such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (calculator 1) to calculate eGFR. (See 'Accurate estimation of kidney function' below.)

As noted below, hydroxyurea can interfere with serum creatinine measurement by the i-STAT device; patients receiving hydroxyurea who have an increased serum creatinine measurement using the i-STAT device should have a repeat measurement by another method. (See 'Role of hydroxyurea and transfusions' below.)

•Individuals with SCD can develop proximal and distal renal tubular acidosis (RTA) that is characterized by low carbon dioxide (CO₂) and abnormal potassium levels, and occasionally hyperchloremia [59]. In addition, iron chelating agents may cause Fanconi syndrome (generalized proximal tubular dysfunction), which may affect calcium and phosphate levels in the blood and urine [60,61]. These individuals should have correction of their acidosis with bicarbonate as well as appropriate treatment for the RTA. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Fanconi syndrome'.)

•If the eGFR declines by more than 10 percent in a given year or drops below 60 mL/min/1.73 m², we evaluate the urine sediment and perform kidney imaging [3].

•Cystatin C has been suggested as a useful marker that may be of value in selected cases, but it has not been validated for routine testing [62,63].

•In research settings, technetium-DTPA measurements have been used; however, DTPA may underestimate GFR due to plasma protein binding.

●Kidney imaging (eg, ultrasound) is appropriate and part of the routine evaluation for individuals with SCD who have an acute or chronic decline in kidney function (eg, by more than 10 percent), significant hematuria or proteinuria, or any clinical symptoms or other findings consistent with urinary obstruction. The main purpose is to identify obstructive uropathy or other anatomic abnormalities. As noted below, ultrasound is not sensitive for renal medullary carcinoma, and individuals with persistent hematuria or other concerning symptoms should have computed tomography (CT) imaging. (See 'Evaluation of hematuria and flank pain' below.)

Certain individuals require more frequent monitoring of kidney function (eg, individuals receiving iron chelation with deferasirox should have a monthly metabolic panel and urine albumin and creatinine; those receiving deferoxamine should have this testing every three months). Dose reduction or temporary discontinuation may be required for significant increases in creatinine. (See 'Avoiding medications that are toxic to the kidney' below and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy'.)

This approach is largely consistent with guidance from a National Heart, Lung, and Blood Institute (NHLBI) expert panel, which recommends initial screening for proteinuria beginning by age 10 years. We start assessing for proteinuria at age five or six years, because our clinical experience along with that of others demonstrates that persistent proteinuria can occur before the age of 10 years [32]. We suggest annual surveillance for those without evidence of proteinuria and referral of individuals with proteinuria (urine albumin-to-creatinine ratio of >300 mg/g or >300 mg/24 hours) to a nephrologist [10,64]. The panel expressed some reservations regarding the appropriate testing but also presented a consensus view that many of the assessments for kidney disease have relatively low costs and burdens, and the potential for benefit is high if renal dysfunction is detected and treated early.

The usefulness of kidney biopsy has not been evaluated in SCD, and the decision to biopsy the kidney is individualized, similar to the general population [3,10]. As noted above, markers of early kidney disease are sought but have not been validated and are not used routinely. (See 'Pathogenesis' above and "The kidney biopsy", section on 'Indications'.)

Additional testing for atypical presentations — Individuals with atypical presentations (eg, more severe proteinuria, proteinuria plus hematuria, decline in hemoglobin out of proportion to severity of reduced kidney function) may require additional testing [3].

Examples include the following:

●For individuals over age 40 who develop new or worsening kidney dysfunction, testing for multiple myeloma with a serum protein electrophoresis (SPEP) and urine protein electrophoresis, immunofixation, and serum free light chain assay is appropriate. (See "Laboratory methods for analyzing monoclonal proteins".)

●For individuals with new-onset nephrotic syndrome, recent transient red cell aplasia, or liver function test abnormalities, testing for parvovirus B19, viral hepatitis (hepatitis B or C), and/or HIV may be helpful. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Evaluation of nephrotic syndrome'.)

●For individuals with systemic lupus erythematosus (SLE) or SLE-like features, testing for kidney involvement is done periodically, including urinalysis and examination of the urine sediment, anti-DNA antibody titers, and other markers of disease activity. Kidney biopsy is often performed. Details are presented separately. (See "Lupus nephritis: Diagnosis and classification", section on 'Evaluation and diagnosis'.)

Diagnosis — The diagnosis of SCN is made in an individual with kidney dysfunction (eg, decline in eGFR, proteinuria) without another explanation after a thorough evaluation for other causes of these findings (ie, it is a diagnosis of exclusion). The extent of the evaluation depends on the patient's age and clinical status as discussed above. (See 'Routine surveillance and early detection' above and 'Additional testing for atypical presentations' above.)

Accurate estimation of kidney function — Accurate determination of kidney function is critical to determining the need for interventions. Calculation of the eGFR as discussed above is used to estimate kidney function in patients with SCD. (See 'Routine surveillance and early detection' above.)

Potential sources of interference in estimating GFR in SCD include the following:

●Glomerular hyperfiltration and supranormal proximal tubule function may lower the serum creatinine and suggest kidney function is better than it is. In a study involving 19 individuals with SCD, the creatinine clearance overestimated the measured GFR by 29 percent (154 versus 119 mL/min), roughly twice the percent difference in a group of eight age- and sex-matched controls [65]. The Schwartz formula was designed to minimize such inaccuracy in estimating GFR; however, it has limitations. Even the CKD-EPI equation was shown to have overestimated GFR by approximately 45 mL/min/1.73 m² [66]. (See 'Pathogenesis' above.)

●Hydroxyurea interferes with one device (the i-STAT device) that measures serum creatinine and is used in certain clinical laboratories. (See 'Role of hydroxyurea and transfusions' below.)

●Other medications that may falsely affect the estimated GFR are listed separately. (See "Drugs that elevate the serum creatinine concentration".)

The use of cystatin C may be useful in some individuals and may correlate better with GFR, although it has not been validated specifically in SCD across different age groups. In a series of 98 individuals with SCD, cystatin C was well-correlated with measured GFR [63]. The cystatin C-based CKD-EPI showed the greatest agreement with GFR compared with other CKD-EPI equations.

Additional discussions of this subject are presented separately. (See "Chronic kidney disease in children: Clinical manifestations and evaluation", section on 'Serum creatinine and GFR' and "Assessment of kidney function" and "Calculation of the creatinine clearance".)

Prevention and management (sickle nephropathy) — Lack of access to early multidisciplinary care contributes to increased mortality in SCD, and a significant proportion of this early mortality is related to sickle nephropathy. It is especially important to ensure that individuals with SCD have timely access to preventive therapies and to replacement therapy (dialysis or kidney transplantation) when needed.

Avoiding medications that are toxic to the kidney — The following medications are often used in SCD and are potentially nephrotoxic:

●NSAIDs – Nonsteroidal antiinflammatory drugs (NSAIDs), including ketorolac, may be over-used for pain. In some cases, short-term use of NSAIDs may be appropriate; however, routine use of NSAIDs for fever, minor pain, or as an adjunct to opioids, should generally be avoided due to the increased risks of acute and chronic kidney injury. Families should be counseled to use acetaminophen instead of NSAIDs for fever and routine minor pains.

Vaso-occlusive pain management is an especially challenging area for individuals with SCD. Opioid pain medications and other means of pain control should be available and given in appropriate doses as needed. High doses of NSAIDs, especially ketorolac, should be minimized or avoided during hospitalization, as discussed separately. Hydroxyurea may reduce the frequency of painful episodes but can take months to become effective, and appropriate pain medications should not be withheld while awaiting the beneficial effects of hydroxyurea. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Therapies we do not use'.)

●Aminoglycoside antibiotics – Broad spectrum antibiotics including vancomycin and gentamicin are often required for fever, which could be a sign of life-threatening infection. Gram-positive coverage may be especially important in those with indwelling venous catheters. The serum creatinine is a useful test for estimating eGFR, but caveats should be kept in mind. (See 'Accurate estimation of kidney function' above.)

Close attention to dosing and drug levels is essential to prevent drug accumulation. Attention to volume status is also important. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

●Radiocontrast material – Contrast-enhanced imaging studies may be needed to evaluate suspected acute chest syndrome, splenic or hepatic sequestration, or stroke. Radiocontrast material used in computed tomography (CT) scans can also increase the risk for acute kidney injury (AKI) in patients with severely impaired kidney function (ie, eGFR <30 mL/min/1.73 m²); close attention should be paid to adequate hydration and using the smallest dose necessary. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography", section on 'Patients with impaired kidney function'.)

●Iron chelators – Chelation therapy to remove excess iron stores (typically, from transfusional iron overload) are often needed. The oral iron chelator deferasirox causes a known dose-dependent rise in serum creatinine, but this appears to be reversible with close monitoring and discontinuation if the creatinine rises more than 50 percent over baseline or more than two times the upper limit of the reference range. Dose reduction is used for smaller increases in creatinine. Deferasirox also has a Boxed Warning stating that it can cause AKI, especially in individuals with comorbidities. Details are discussed separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy'.)

●Others – Other medications to be avoided if possible include certain chemotherapeutic agents, amphotericin, beta-lactam antibiotics, and certain immunosuppressive drugs [67].

The anticoagulant edoxaban (a direct factor Xa inhibitor) is not nephrotoxic, but there are concerns with its use in individuals with hyperfiltration (creatinine clearance >95 mL/min). If anticoagulation is needed for venous thromboembolism (VTE) or atrial fibrillation, we make sure to adhere to specific dosing recommendations or to use a different anticoagulant. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Edoxaban'.)

Role of hydroxyurea and transfusions — Hydroxyurea is protective against many SCD complications, and its use is appropriate in most individuals with SCD who have vaso-occlusive complications. Hydroxyurea is a mainstay of SCD therapy and is recommended for infants as young as nine months of age who have homozygous hemoglobin SS or sickle-beta⁰ thalassemia. High-quality evidence has demonstrated reduction of several types of vaso-occlusive events. Further details of its mechanism of action, evidence for efficacy, administration, and adverse effects are presented separately. (See "Hydroxyurea use in sickle cell disease".)

For those not receiving hydroxyurea, it is important that they be made aware of the potential benefits as well as the risks; in some cases, the perceived risks may not be supported by available evidence (see "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'). Except for women and men who are actively attempting to conceive a child, for most individuals with signs of SCN (eg, declining eGFR, albuminuria) or significant risk factors for SCN such as hypertension, the hemolysis phenotype, high exposure to potentially nephrotoxic medications, or a history of acute kidney injury, we suggest hydroxyurea.

Evidence for improvement in kidney function with hydroxyurea therapy comes from observational studies and indirect outcomes in randomized trials. As examples:

●Infants and children – The BABY HUG trial, which involved 193 infants (median age, 13.8 months) with sickle cell anemia treated with hydroxyurea or placebo for two years, found indirect evidence of improved kidney function with hydroxyurea (increased urine osmolality and decreased kidney volume on ultrasound) but no significant effect on GFR [68]. Another study suggested that hydroxyurea reduces hyperfiltration in children [36].

●Adults – In a series of 112 adults in a comprehensive sickle cell program, those receiving hydroxyurea had lower rates of albuminuria (35 percent, versus 55 percent in those not receiving hydroxyurea) [69].

Other studies and case reports have also described improvement in kidney function with hydroxyurea and worsening of kidney function when hydroxyurea was discontinued [3,70].

Hydroxyurea can be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB); in fact, the combination of hydroxyurea plus one of these agents may lead to further reduction of proteinuria [69,71,72].

Hydroxyurea is renally metabolized and removed by hemodialysis; dose adjustments may be needed in individuals with reduced kidney function. It has been recommended that individuals undergoing hemodialysis who are initiating hydroxyurea use a lower starting dose (eg, 7.5 mg/kg daily rather than 15 mg/kg daily) [7]. On dialysis days, hydroxyurea should be given after dialysis. Information about dose titration is presented separately. (See "Hydroxyurea use in sickle cell disease", section on 'Monitoring and dose titration'.)

Clinicians should be aware that patients receiving hydroxyurea may have falsely elevated creatinine measurement when using a point-of-care device for measuring serum creatinine (the i-STAT system, used for routine testing in some clinical laboratories) [73]. In such cases, a method of creatinine measurement other than the i-STAT should be used. (See 'Accurate estimation of kidney function' above.)

Transfusions are not used to treat acute kidney injury (AKI) or CKD. However, case reports have described improvement or stabilization of renal function in selected individuals treated with regular transfusions for other indications [3,74]. In some cases, individuals with SCD and ESKD who have severe anemia that is unresponsive to erythropoiesis-stimulating agents (ESAs) may be treated with transfusions while awaiting other therapies [3]. (See 'ESKD interventions (dialysis and transplant)' below.)

Nephrologist referral and CKD interventions — Referral to a nephrologist may be appropriate for any of the following [10]:

●Decline in kidney function or development of proteinuria (eg, positive urine dipstick for protein), even if eGFR remains within the reference range

●eGFR below 60 mL/min/1.73 m²

●Any degree of albuminuria in a child

●Hematuria, especially if persistent

●Hypertension or relative hypertension

There have been very few randomized trials addressing optimal therapy in individuals with proteinuria and hypertension [75]. However, available evidence supports the use of an ACE inhibitor or an ARB:

●A small trial randomly assigned 22 individuals with SCD who had moderately increased albuminuria and normal blood pressure to receive captopril 25 mg daily or placebo for six months [76]. The captopril group had a small decrease in proteinuria (by 45 mg per 24 hours), while the placebo group had an increase in proteinuria (by 18 mg per 24 hours). The captopril group had a small change in blood pressure.

●Several observational studies have also described improvements in moderately increased albuminuria, less rapid decline in eGFR in individuals with SCD when treated with ACE inhibitors or ARBs, and worsening when ACE inhibitors were discontinued [47,77,78]. One of these was a retrospective study of 86 individuals with SCD who were followed for over 2 years while receiving one of these agents compared with 68 individuals not receiving an agent to block the renin-angiotensin-aldosterone system; the study demonstrated a reduction in the development in chronic kidney disease and a trend towards reduced proteinuria associated with the ACE inhibitor or ARB [78].

●There is good evidence in the non-SCD population that reductions in moderately increased albuminuria (for individuals with >500 to 1000 mg/day proteinuria) and control of blood pressure with an ACE inhibitor or an ARB slows the progression to ESKD, and the same benefits would be expected in SCD. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of antihypertensive drugs on proteinuria'.)

Kidney failure is a morbid common complication in SCD. Evidence-based, long-term trials of the benefit of treating proteinuria in SCD are not available. However, our consensus recommendations are to initiate treatment with an ACE inhibitor or ARB when there is persistent urine protein >500 mg per day, and especially when the urine protein to creatinine ratio (uPCR) is >100 mg/mmol (>884 mg/g), which is approximately equivalent to urine protein ≥1000 mg per day. This treatment includes patients who do not have hypertension. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Close monitoring of the blood pressure is essential to avoid hypotension. Supporting evidence in the non-SCD population, goals of therapy, details of administration, and adverse effects are presented separately; it is especially important to monitor the blood pressure closely in individuals with SCD because these individuals often have low blood pressure. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Goal blood pressure in adults with hypertension", section on 'Patients with chronic kidney disease' and 'Hypotension' below.)

Other interventions to correct metabolic abnormalities (eg, hydration, calcium supplementation, phosphate binders, potassium restriction) and to slow the rate of CKD progression (protein restriction, smoking cessation, and glycemic control), as well as treatment of the complications of renal failure (eg, volume overload, neuropathy, uremic bleeding, pericarditis) are similar to individuals without SCD and are discussed in detail separately. (See "Chronic kidney disease in children: Overview of management" and "Overview of the management of chronic kidney disease in adults".)

Regular transfusions have been suggested for individuals with worsening kidney function approaching the need for kidney transplantation, especially if their anemia is no longer responsive to ESAs [3]. In a cohort study of African American ESKD patients initiating dialysis during the period from 2000 to 2014, high-dose ESA and severity of anemia were both risk factors for worse outcomes for EKSD [79].

While transfusions are avoided in the non-SCD population to minimize the risk of immunologic sensitization and potential adverse effects on future transplantation, this is not realistic in most people with SCD, who are often transfused for a number of complications. Transfusions should be used when indicated, with appropriate precautions to minimize alloimmunization; these are discussed in more detail separately. Leukocyte-reduced blood products have been demonstrated to reduce the risk of antibody-mediated kidney allograft rejection [80]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion' and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Transfusion techniques'.)

ESKD interventions (dialysis and transplant) — Replacement therapy (dialysis or kidney transplantation) is appropriate for individuals with SCD who develop end-stage kidney disease (ESKD), similar to the general population. (See "Indications for initiation of dialysis in chronic kidney disease" and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)

●Dialysis – Individuals with SCD and ESKD can be treated successfully with hemodialysis or peritoneal dialysis [3]. Dialysis is generally initiated at a younger age in individuals with SCD than in the general population. In a cohort of 397 individuals with SCN, the median age at which ESKD developed was 41±14 years [81]. The choice between hemodialysis and peritoneal dialysis depends on clinical factors and patient preferences. For those who are also receiving transfusions, the same vascular access can be used for hemodialysis; discussion between the nephrologist and hematologist before placement of dialysis access or a venous catheter for transfusion is advised to ensure that the device used is appropriate for both. The incidence of hemodialysis-related complications does not appear to be different in SCD compared with the general population, although survival appears to be decreased [7,82].

SCD and hemodialysis are both risk factors for pulmonary hypertension. This high risk should be addressed by evaluation of pulmonary status before placement of dialysis access. Separate topic reviews discuss the symptoms of pulmonary hypertension (eg, dyspnea, chest pain, exercise intolerance) and the appropriate evaluations. (See "Pulmonary hypertension associated with sickle cell disease" and "Pulmonary hypertension in patients with end-stage kidney disease" and "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

●Kidney transplantation – Kidney transplantation offers the best outcome for individuals with ESKD from SCN and should be offered to all potential candidates [83].

•In a 2009 series involving 237 individuals with SCD who underwent kidney transplantation, the 10-year survival was 56 percent [84]. By comparison, those with ESKD who did not receive a transplant had a 10-year survival of 14 percent. In a subsequent study that compared survival rates over time, the six-year survival increased between an earlier era (from 1988 to 1999; median survival, 56 percent) to a later era (from 2000 to 2011; median survival, 70 percent) [85].

•A large case series of individuals with ESKD reported that those with SCD were less likely to be placed on a kidney transplant waiting list, which may account for decreased survival from ESKD in the SCD population [81].

Several explanations exist for the lower rates of transplantation in SCD, including racial bias, concerns about higher infectious risk, concerns about blood group incompatibility that may lead to rejection, concerns about pulmonary hypertension, and concerns about side effects of immunosuppressive drugs (eg, avascular necrosis of bone as a complication of glucocorticoids); none of these should be reasons for avoiding transplantation [86]. (See 'Prognosis' below.)

Pulmonary hypertension in kidney transplant candidates is discussed separately. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Pulmonary disease'.)

Recommended perioperative interventions include using transfusion to a preoperative hemoglobin level of no more than 10 g/dL; using exchange transfusion to avoid hyperviscosity when appropriate; minimizing alloimmunization by using antigen-matched blood; and paying close attention to oxygenation, hydration, respiratory status, and pain control [87]. Attention must be paid to the increased risks of VTE and the greater risk of infection related to functional asplenia. ESKD typically reduces the efficacy of vaccinations, and boosters may be needed prior to transplant [7]. Transfusion and infectious disease considerations are discussed in more detail separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques" and "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention'.)

Typical graft survival at one year appears to be approximately 67 to 82 percent [87]. SCN can occur in the transplanted kidney unless the underlying disease process is altered (eg, with hematopoietic stem cell transplantation or disease-modifying therapies [84,88,89]).

As noted below and in separate topic reviews, evaluation for hyperkalemia and its appropriate treatment should be undertaken. (See 'Hyperuricemia and hyperkalemia' below and "Management of hyperkalemia in children" and "Treatment and prevention of hyperkalemia in adults".)

Anemia interventions — SCD causes chronic hemolytic anemia at baseline and lower erythropoietin and baseline hemoglobin levels [90]; thus, the threshold for interventions to increase the hemoglobin level differs from non-SCD individuals. The optimal hemoglobin level for an individual with SCD and ESKD is unknown, and there are no good outcomes data for the use of erythropoiesis-stimulating agents (ESAs; eg, erythropoietin).

For individuals with SCD and CKD who develop worsening anemia, especially with a decrease in reticulocyte count, use of an ESA such as epoetin or darbepoetin is appropriate. These medications can be given concurrently with hydroxyurea, and there is a theoretical possibility that concurrent use may reduce the risk of adverse events related to the ESA. Some studies have suggested that epoetin may trigger vaso-occlusion and/or VTE, although this was not borne out in a retrospective analysis [91].

ESA doses and schedules of administration have varied in different case series, as summarized in a review article from 2016 [7]. Choice of ESA, dosing, and adverse effects are presented in detail separately. (See "Treatment of anemia in nondialysis chronic kidney disease".)

Important caveats related to the use of ESAs in individuals with SCD include the following [7]:

●Avoid hyperviscosity – Complications of hyperviscosity (vaso-occlusion, stroke, or VTE) may occur if the hemoglobin level is too high, especially in individuals with HbSC disease. We generally try to avoid an increase in hemoglobin of more than 1 g/dL in a two-week period and generally target a hemoglobin level not higher than 10 g/dL (hematocrit 30 percent) when the HbS is >35 percent of total hemoglobin. Some experts prefer to target a hemoglobin level that does not exceed 8 to 9 g/dL in individuals with frequent pain episodes or other frequent vaso-occlusive complications.

●Avoid iron overload – Individuals with SCD often have iron overload and may be receiving iron chelation therapy. Routine treatment with supplemental iron is not appropriate; however, iron replacement therapy should be administered if an individual with SCD develops iron deficiency. (See "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients" and "Treatment of iron deficiency in dialysis patients" and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy'.)

Individuals with SCD are also frequently treated with transfusions preoperatively or in the setting of certain acute vaso-occlusive complications. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Prognosis — SCN has been estimated to contribute substantially to morbidity and mortality in SCD.

Individuals with SCD who have acute kidney injury have a greater risk of death from COVID-19 [92].

ESKD accounts for approximately 16 to 18 percent of deaths in some series [6]. In a study from 1991, CKD developed in approximately 4 percent of individuals with HbSS disease, and death occurred at approximately four years after the development of kidney failure (at a median age of 27 years) [48]. Median survival among patients with and without kidney failure was 29 and 51 years, respectively. The mortality risk of patients with kidney failure was similar to those who had had a stroke.

Survival is substantially decreased among patients with kidney failure and SCD compared with those with kidney failure without SCD. The unadjusted five-year risk of death in patients with SCD and ESKD was significantly elevated compared with the reference population (hazard ratio [HR], 2.00; 95% CI: 1.66-2.40) [79]. However, one analysis found that this reduced survival did not persist when adjusted for the lower rate of kidney transplantation in SCD [81,86]. Lack of access to multidisciplinary care may also contribute to worse survival [2]. Typical survival one year after kidney transplantation is approximately 88 percent [87].

These observations highlight the importance of comprehensive care during all stages of life as well as the need for disease-modifying therapies that can prevent complications of SCD. (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care" and "Overview of the management and prognosis of sickle cell disease" and "Investigational therapies for sickle cell disease".)

OTHER DISEASE COMPLICATIONS

Hematuria and/or flank pain

Evaluation of hematuria and flank pain — Hematuria is one of the more common findings in SCD, occurring in approximately 6 percent of children and a large but unknown proportion of adults [93]. There are a number of possible causes ranging from benign to serious. Hematuria is also common in individuals with sickle cell trait, as discussed separately. (See "Sickle cell trait", section on 'Urologic and kidney disease'.)

All individuals with SCD (or sickle cell trait) who develop microscopic or macroscopic hematuria should be evaluated for the cause; this finding should not merely be attributed to the underlying disease. (See "Evaluation of gross hematuria in children" and "Etiology and evaluation of hematuria in adults".)

Common causes of hematuria and flank pain in SCD (and sickle cell trait) include renal papillary necrosis (RPN) and urinary tract infections (UTIs). As discussed below, renal medullary carcinoma (RMC) is a rare aggressive malignancy that should be considered in any individual with unexplained hematuria. (See 'Renal infarction and papillary necrosis' below and 'UTI and pyelonephritis' below and 'Renal medullary carcinoma' below.)

The evaluation of microscopic hematuria is discussed separately. (See "Evaluation of microscopic hematuria in children" and "Etiology and evaluation of hematuria in adults".)

For macroscopic (gross) hematuria, the evaluation includes urinalysis, culture, and typically renal ultrasound to evaluate for papillary necrosis, kidney stones, and other kidney lesions. As with any individual who presents with bleeding, impaired hemostasis should be ruled out as a contributing factor with testing such as coagulation studies, platelet count, and other testing as indicated based on the type and severity of bleeding. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

All individuals with SCD who have hematuria that does not resolve should undergo computed tomography (CT) scanning to evaluate for renal medullary carcinoma, as the sensitivity of ultrasound for this malignancy is low and the only opportunity for cure is early detection. (See 'Renal medullary carcinoma' below and "Etiology and evaluation of hematuria in adults", section on 'Selection of modality'.)

Renal infarction and papillary necrosis — Infarction and RPN are common in sickle cell nephropathy (SCN), seen in as many as 23 to 40 percent of individuals [94,95]. Contributing factors include interstitial nephritis, acute pyelonephritis, obstructive uropathy, diabetes mellitus, or analgesic use.

The bleeding is typically mild, painless, and self-limited [8]. It may be complicated by urinary tract obstruction or infection [29,96]. Acute segmental or total renal infarcts may present with nausea, vomiting, flank or abdominal pain, fever, and hypertension (presumably renin-mediated) [97,98].

Renal infarction and RPN are generally diagnoses of exclusion but can be detected by imaging in many cases; other causes of hematuria and/or abdominal or flank pain need to be eliminated before these findings can be attributed to RPN.

Kidney ultrasound is a useful initial test; it typically shows increased echogenicity of the inner medulla and, in more advanced cases, a filling defect in the area of the medullary tip. Definitive diagnosis requires CT. CT may be omitted in selected individuals with symptoms that are milder or less concerning. Re-imaging is not required unless there are specific findings such as obstruction or the need for urologic intervention [99].

Management depends on the degree of hematuria:

●For microscopic hematuria, hydration is often adequate treatment in the short term.

●For macroscopic hematuria, bedrest and aggressive hydration are often used.

•Bedrest is intended to avoid dislodging blood clots.

•Hydration and alkalization of the urine may be used to reduce the toxicity from heme pigment, and diuretics may be used to increase the urinary flow rate. The rationale and details of therapy are discussed separately. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Prevention'.)

•Exchange blood transfusion may be used to lower the percentage of hemoglobin S in some cases. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

●For severe or refractory hematuria, a number of other interventions have been described in case reports, although none of these have been studied in detail. These include:

•Desmopressin (DDAVP) [100]

•An antifibrinolytic agent (eg, tranexamic acid [TXA], epsilon-aminocaproic acid [EACA]) [101-103]

•Embolization of the involved vessel or balloon tamponade [104]

Unilateral nephrectomy has been performed but is not recommended because bleeding can recur in the remaining kidney.

Antifibrinolytic therapy was previously reserved for individuals for whom other therapies have been ineffective, due to the risk of urinary obstruction from clots in the collecting system. However, we have used low-dose antifibrinolytic therapy in individuals with hematuria due to papillary necrosis and have found it to be safe and effective, as discussed below [102]. (See 'Clinical vignettes' below.)

Any individual with infarction or RPN significant enough to cause hematuria who is not already receiving hydroxyurea should discuss the potential benefits, which in most cases are likely to outweigh the risks.

UTI and pyelonephritis — Urinary tract infections (UTIs) and pyelonephritis are more common in individuals with SCD than those in the general population [96]. The mechanisms may include higher rates of volume depletion and urinary tract obstruction or inflammation related to infarction or papillary necrosis. These infections are especially concerning because individuals with SCD are functionally asplenic and at risk of sepsis from encapsulated organisms.

UTI or pyelonephritis may precipitate vaso-occlusive complications, and it is important to consider these (and other) infections in individuals presenting with pain, especially if atypical for their usual vaso-occlusive pain. (See "Evaluation of acute pain in sickle cell disease".)

This is particularly important in children, who often do not present with typical urinary tract symptoms such as urinary urgency, frequency, or dysuria, and in individuals with an indwelling urinary catheter. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Clinical presentation' and "Catheter-associated urinary tract infection in adults".)

These infections should also be suspected in an individual who presents with hematuria, dysuria, flank pain, abdominal pain, nausea/vomiting, and/or other systemic symptoms. Evaluation should include urinalysis with culture and sensitivities, imaging to assess for ureteral obstruction, as well as pregnancy testing for women of childbearing potential. (See "Acute infectious cystitis: Clinical features and diagnosis in children older than two years and adolescents" and "Acute complicated urinary tract infection (including pyelonephritis) in adults".)

All individuals with SCD who present with fever should be treated promptly (within 60 minutes, preferably after cultures have been obtained). Individuals with SCD who have fever are often advised to have antibiotics available at home. Antibiotic regimens should include appropriate coverage for likely pathogens and encapsulated organisms, as discussed in separate topic reviews. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function", section on 'Evaluation and management'.)

Renal medullary carcinoma — RMC is a rare, highly aggressive non-clear-cell kidney cancer predominately found in people with sickle cell trait [105-109]. The typical onset is in early adulthood, and men are affected approximately twice as frequently as women [110]. Presenting findings include flank pain and hematuria; some individuals have a palpable mass, with right kidney involvement more common than left [106]. The disease is highly aggressive and often metastatic on presentation [107].

The biologic basis for the unique features of RMC have not been fully explained, but loss of expression of the chromatin remodeling factor SMARCB1 appears to be important [111,112].

RMC is not restricted to those with sickle cell trait; it can also occur in individuals with SCD, and clinicians should have a low threshold for considering the diagnosis in an individual with flank pain and/or hematuria [110,113]. RMC may appear as a cyst on ultrasound; this should be further evaluated with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) [114]. Scans for metastatic disease should be obtained in patients who are found to have RMC.

The optimal management of RMC is unknown. Nephrectomy is usually performed, and chemotherapy or targeted (biologic) therapy is often administered. The tumors appear to be platinum-sensitive [115-117]. Inhibitors of programmed cell death protein 1 (PD-1) such as pembrolizumab and nivolumab are under investigation, and enrollment in a clinical trial is encouraged [118]. (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Collecting duct and renal medullary carcinoma'.)

The prognosis for RMC is poor. In a 2017 series of 52 individuals with RMC, 38 (73 percent) underwent nephrectomy [119]. Median survival was 16 months in those who had a nephrectomy and seven months in those who did not. Seven (13 percent) survived beyond two years.

Acute kidney injury — Acute kidney injury (AKI; eg, decline in urine output or rise in serum creatinine by ≥0.3 mg/dL developing within hours to days) occurs in as many as 17 percent of children and 10 percent of adults with SCD who present to the hospital [120,121].

In a Pediatric Health Information System database review that included pediatric admission for vaso-occlusive pain events, 2.5 percent of admissions were complicated by AKI [122]. AKI was associated with increased likelihood of admission to the intensive care unit, longer hospitalization, and increased likelihood of readmission.

In another study, the incidence of AKI during vaso-occlusive pain episodes was approximately 4 percent and appeared to be limited to those with acute chest syndrome and pulmonary hypertension, suggesting a potential role for right ventricular dysfunction and venous congestion [123].

There are a number of potential causes of AKI in SCD:

●Hypovolemia due to dehydration, infection, or splenic sequestration

●Rhabdomyolysis

●Nephrotoxic medications

●Renal vein thrombosis

●Urinary tract obstruction (eg, due to blood clots)

●Hepatorenal syndrome related to hepatic failure from iron overload

Individuals with SCD can also develop AKI for any of the reasons that apply to the general population. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Evaluation of acute kidney injury among hospitalized adult patients" and "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)

The prognosis for individual episodes of AKI appears to be favorable, with 10 of 12 individuals (83 percent) having recovery of kidney function in one series [120]. However, repeated episodes of acute or subacute kidney injury may contribute to the development of chronic kidney disease. (See 'Pathogenesis' above.)

Evaluation and standard interventions for AKI are similar to the general population and include thorough history and physical examination, examination of the urine chemistry and sediment, and imaging of the kidneys (algorithm 1). Comprehensive discussions of the general approach are presented separately. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis" and "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Evaluation of acute kidney injury among hospitalized adult patients".)

The same indications for dialysis in AKI are used in SCD as in individuals in the general population. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

There is no evidence to suggest that transfusion improves outcomes in individuals with SCD who develop AKI. A 2014 National Heart, Lung, and Blood Institute (NHLBI) guideline on the management of SCD made a consensus recommendation that transfusions not be used in AKI unless there are other indications (eg, symptomatic anemia, splenic sequestration, acute chest syndrome, acute stroke) [10,64]. These and other indications are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Blood pressure abnormalities

Hypotension — Hypotension is more common in SCD than the general population [124]. Proposed mechanisms include prostaglandin-mediated changes in vascular tone and salt reabsorption [65,124]. Individuals with impaired urinary concentration (hyposthenuria) are at higher risk for volume depletion and may have less ability to compensate for a reduction in oral intake by increasing water retention in the kidney [10].

In patients whose baseline blood pressure readings are typically low, relatively "normal" blood pressure readings may actually represent significant hypertension, with attendant risks of adverse cardiovascular outcomes. Likewise, the use of antihypertensive agents to lower intraglomerular pressure may result in more severe hypotension than in the general population.

As a result, it is important to ensure adequate hydration, especially during acute pain episodes, acute chest syndrome, or infections, when oral intake may be decreased and insensible water losses may be increased. (See "Overview of the management and prognosis of sickle cell disease", section on 'Hydration'.)

Hypertension — The incidence of hypertension in SCD is markedly lower than in the general population of Black individuals (2 to 6 percent versus 28 percent). The challenge in making the diagnosis of hypertension in children and adults with SCD is that SCD is associated with a decrease in blood pressure [125-127]. Furthermore, higher systolic blood pressures (typically not considered in the hypertension range) are associated with earlier mortality, strokes, silent strokes, elevated tricuspid jet velocity, and chronic kidney disease [127-131].

All individuals with SCD should be closely monitored for the development of relative hypertension and masked hypertension. The pulse pressure is emerging as an important factor for consideration as well. (See "Increased pulse pressure".)

Risk factors for hypertension such as nocturnal hypoxemia, which is common in the SCD population, as well as other risk factors seen in non-SCD populations (eg, high body mass index, high dietary sodium intake), should be sought and addressed appropriately. Sleep studies should be obtained in selected individuals with suspected nocturnal desaturation. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Sleep disordered breathing and nocturnal hypoxemia' and "Overview of hypertension in adults", section on 'Risk factors for primary (essential) hypertension'.)

For those with hypertension, management involves nonpharmacologic interventions such as weight loss (if overweight), salt restriction (<100 mEq [2.3 g of sodium or 6 g of sodium chloride]/day), and exercise, similar to the non-SCD population. For those with reproducible hypertension, an antihypertensive medication is initiated with a goal blood pressure of ≤130/80. (See "Overview of hypertension in acute and chronic kidney disease" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Antihypertensive medications should be used judiciously in individuals with SCD due to the risks of hypotension and volume depletion. For individuals with SCD who require antihypertensive medications, we usually use an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). The rationale is that these agents reduce proteinuria and lessen the likelihood of progression to end-stage kidney disease, as noted above. Individuals with peripheral or pulmonary edema are also treated with a loop diuretic or dialysis if indicated (indications the same as in the non-SCD population). Individuals without proteinuria may be treated with a renin-angiotensin or an ACE inhibitor, an ARB, or, if edema is present, a diuretic. The rationale for these choices and options for second- and third-line therapy are presented separately. (See 'Nephrologist referral and CKD interventions' above.)

Hyperuricemia and hyperkalemia — Hyperuricemia and gout may be an early sign of chronic kidney disease with impaired uric acid excretion [10]. Joint pain from gout may be mistakenly attributed to vaso-occlusive pain. (See "Pathophysiology of gout", section on 'Hyperuricemia and gout' and "Evaluation of acute pain in sickle cell disease".)

Details of the evaluation and management of gout are presented separately. (See "Clinical manifestations and diagnosis of gout" and "Treatment of gout flares" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)

Hyperkalemia is often a secondary effect from untreated metabolic acidosis and possibly renal tubular acidosis in individuals with SCD. Hyperkalemia may also complicate acute or chronic kidney disease. (See "Causes and evaluation of hyperkalemia in adults", section on 'Acute and chronic kidney disease'.)

Severe hemolysis can also cause hyperkalemia or contribute to hyperkalemia in individuals with underlying kidney disease (eg, after transfusion). The hyperkalemia in these cases is often transient and resolves with treatment of the underlying condition. It is also possible for hemolysis to occur at the time of the blood draw (eg, due to hemolysis in the collection needle), and unexpected increases in serum potassium should be confirmed by repeat testing with attention to minimizing hemolysis. (See "Causes and evaluation of hyperkalemia in adults", section on 'Pseudohyperkalemia'.)

For severe hyperkalemia (eg, with concern about arrhythmias), management is the same as in the non-SCD population, as discussed in separate topic reviews. (See "Management of hyperkalemia in children" and "Treatment and prevention of hyperkalemia in adults".)

Enuresis — Enuresis (nighttime bedwetting) is more common in children and young adults with SCD compared with age-matched controls, with prevalences as high as 9 percent [132-134]. A number of potential causes may contribute including hyposthenuria, sleep-disordered breathing, and psychological stress. (See 'Pathogenesis' above and "Overview of the pulmonary complications of sickle cell disease".)

Evaluation and management are similar to that in individuals without SCD; there should be a lower threshold for asking patients and parents about this symptom. (See "Nocturnal enuresis in children: Etiology and evaluation" and "Nocturnal enuresis in children: Management" and "Nocturia: Clinical presentation, evaluation, and management in adults".)

Priapism and erectile dysfunction — Priapism (unwanted or sustained erection in the absence of sexual activity) is a known complication of SCD that does not appear to correlate with other urinary complications. Repeated episodes of priapism can lead to erectile dysfunction. The urology or nephrology evaluation is an appropriate time to ask about these symptoms, since some individuals may be reluctant to mention them to their primary clinician. Evaluation and management are discussed separately. (See "Priapism and erectile dysfunction in sickle cell disease".)

CLINICAL VIGNETTES — The following case vignettes illustrate the presentations of selected complications and our approach to evaluating and treating them:

●Renal tubular acidosis – A 25-year-old male with SCD and a history of stroke was receiving chronic transfusion therapy for nine years, with a remarkable recovery from neurologic injury but significant iron overload related to transfusions. He had difficulty adhering to therapy with the iron chelator deferoxamine, which requires nightly continuous infusions for 10 to 12 hours. He switched to deferasirox (25 mg/kg/day) with close monitoring of ferritin and serum chemistries. (See 'Routine surveillance and early detection' above.)

His ferritin improved, but over a period of several months he developed bone pain, generalized weakness, and dehydration that were attributed to his underlying SCD. Subsequently, his serum creatinine increased mildly to 1.2 mg/dL and his urinalysis began to demonstrate proteinuria. Several months later he became confused and short of breath and was rushed to the emergency room, where he was found to have severe acidosis, proteinuria, and urinary potassium wasting (random urinary potassium of 45 mmol/L). He was diagnosed with severe renal tubular acidosis and treated with intravenous bicarbonate and correction of electrolyte abnormalities, as well as stopping the deferasirox, which is known to cause impaired kidney function and renal tubular acidosis. His laboratory parameters returned to normal; however, he continued to require daily potassium and phosphate supplementation. His iron chelation medication was changed to daily deferiprone, with deferoxamine on weekends.

●Papillary necrosis – An 18-year-old African American male with HbSC disease presented to the hospital with flank pain and macroscopic hematuria that was present on awakening from sleep [102]. He had mild thrombocytopenia attributed to hypersplenism (platelet count stable between 68,000 to 78,000/microL) and normal coagulation testing including testing for von Willebrand disease (VWD). Cystourethroscopy showed multiple clots in the bladder and bleeding from the left kidney; these were also present on computed tomography (CT) scanning (with contrast). Ultrasound showed renal papillary necrosis, and CT showed no evidence of a kidney tumor. (See 'Evaluation of hematuria and flank pain' above.)

He was treated with intravenous hydration, bladder irrigation, and exchange transfusions, but he continued to have massive hematuria [102]. Nephrectomy was considered, but in an attempt to avoid nephrectomy, he was treated with low-dose oral epsilon aminocaproic acid (EACA; 50 mg/kg orally every eight hours). Treatment resulted in marked resolution of hematuria within a few hours; however, the creatinine rose from 1.3 to 1.8 mg/dL, leading to cessation of EACA. Kidney ultrasound showed no obstruction, and his urine became grossly bloody, so EACA was restarted at 20 mg/kg every 12 hours. This resulted in cessation of hematuria with a stable creatinine at 1.2 to 1.3 mg/dL. He was able to be discharged home on EACA at a dose of 5 mg/kg orally every eight hours, which he continued for approximately four weeks.

●Renal medullary carcinoma – A 16-year-old African American male with SCD presented with several months of abdominal pain and microscopic hematuria [135]. CT scans showed a primary mass in the kidney with retroperitoneal lymphadenopathy and lesions in the lungs and liver. Biopsy showed renal medullary carcinoma. He was treated with neoadjuvant chemotherapy (carboplatin, gemcitabine, and bortezomib) followed by nephrectomy and palliative radiation for pain. He had a transient response followed by widespread metastatic disease and died 20 months after diagnosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Sickle cell disease and thalassemias".)

SUMMARY AND RECOMMENDATIONS

●Mechanisms of kidney injury – Sickle cell disease (SCD) has several related effects on the kidney, collectively referred to as "sickle cell nephropathy" (SCN) or "sickle nephropathy." Kidney damage is multifactorial and begins in childhood but is often only appreciated retrospectively after the serum creatinine increases beyond the reference range. By adulthood, one-third to one-fourth of individuals are affected. SCN is more frequently seen with severe genotypes (HbSS or sickle-beta⁰ thalassemia) but can also be seen in sickle-beta⁺ thalassemia or HbSC disease. (See 'Pathogenesis' above and 'Prevalence' above.)

●Screening – Screening for SCN is an essential component of management for all individuals with SCD. Typically, routine evaluations including blood pressure, urinalysis including albumin-to-creatinine ratio, and metabolic panel with estimation of glomerular filtration rate (GFR) are initiated between three to five years and no later than 10 years of age. Children are typically seen every four to six months and adults every two to three months. Caveats regarding atypical presentations and accurate estimation of kidney function are noted above. (See 'Evaluation' above.)

●Prevention – Hydroxyurea is the mainstay of treatment in SCD and is recommended for most individuals with vaso-occlusive manifestations, as discussed in detail separately (see "Hydroxyurea use in sickle cell disease"); as a result, most people with SCD will already be taking hydroxyurea. For individuals with SCN or risk factors for SCN such as hypertension who are not already taking hydroxyurea for another SCD indication, we suggest hydroxyurea (Grade 2C). This is likely to reduce proteinuria and delay or prevent the progression of chronic kidney disease (CKD). (See 'Role of hydroxyurea and transfusions' above.)

●Therapy for CKD – For those with hypertension and/or urine protein excretion >500 mg per day, we recommend adding an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Summary and recommendations'.)

This intervention is likely to slow the progression of CKD and to lower the blood pressure. We feel more strongly about the use of an ACE inhibitor or an ARB in those with hypertension or urine protein ≥1000 mg per day (approximately equivalent to a urine protein to creatinine ratio [uPCR] >100 mg/mmol [>884 mg/g]). Importantly, individuals with SCD generally have lower blood pressures than the non-SCD population, and close attention to dosing is needed to avoid hypotension. (See 'Nephrologist referral and CKD interventions' above and 'Hypertension' above.)

●Dialysis and transplant – It is especially important to ensure that individuals with SCD have timely access to preventive therapies and dialysis and/or kidney transplantation when needed. These options are appropriate for individuals with SCD who develop end-stage kidney disease (ESKD). An erythropoiesis-stimulating agent (ESA; eg, erythropoietin) may be used for worsening anemia, but there are important caveats regarding the target hemoglobin level (to avoid hyperviscosity) and the avoidance of routine iron administration, as most individuals with SCD have iron overload. Prognosis with ESKD is poor but should improve with appropriate interventions. (See 'Nephrologist referral and CKD interventions' above and 'ESKD interventions (dialysis and transplant)' above and 'Prognosis' above.)

●Hematuria – Hematuria is common and is often due to renal papillary necrosis (RPN) and/or infection. Rare but concerning is the possibility of renal medullary carcinoma. All individuals with hematuria should have evaluations for these and/or other causes as appropriate. Management depends on the underlying cause and severity of hematuria. (See 'Hematuria and/or flank pain' above.)

●AKI – Acute kidney injury (AKI) is also common and may be due to a number of SCD complications including hypovolemia, rhabdomyolysis, nephrotoxic medications (including NSAIDs, particularly ketorolac), urinary tract obstruction, and others. Management is similar to individuals without SCD. (See 'Acute kidney injury' above.)

●Hypotension – Hypotension is more common and hypertension less common in SCD compared with the general population. Attention should be paid to adequate hydration and judicious use of antihypertensive therapies as indicated. (See 'Blood pressure abnormalities' above.)

●Metabolic and urologic problems – Other findings that may come to attention during the urology or nephrology encounter include hyperuricemia, hyperkalemia, enuresis, priapism, or erectile dysfunction. (See 'Hyperuricemia and hyperkalemia' above and 'Enuresis' above and "Priapism and erectile dysfunction in sickle cell disease".)

ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.