Sickle cell nephropathy

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Sickle cell nephropathy
Specialty Nephrology

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction (papillary necrosis). Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

Contents

In young patients, the disease is characterized by renal hyperperfusion, glomerular hypertrophy, and glomerular hyperfiltration. Many of these individuals eventually develop a glomerulopathy leading to glomerular proteinuria (present in as many as 30%) and, in some, the nephrotic syndrome. Co-inheritance of microdeletions in the -globin gene (thalassemia) appear to protect against the development of nephropathy and are associated with lower mean arterial pressure and less protein in the urine.

Mild increases in the blood levels of nitrogen and uric acid can also develop. Advanced kidney failure and high blood urea levels occur in 10% of cases. Pathologic examination reveals the typical lesion of "hyperfiltration nephropathy" namely, focal segmental glomerular sclerosis. This finding has led to the suggestion that anemia-induced hyperfiltration in childhood is the principal cause of the adult glomerulopathy. Nephron loss secondary to ischemic injury also contributes to the development of azotemia in these patients

Pathophysiology

The development of sickle cell nephropathy (SCN) typically occurs in childhood as seen in the appearance of hyperfiltration and proteinuria. [1] Both are primarily caused by the polymerization of sickle cells in the kidney microvasculature due to the low O2 tension, high osmolarity, and low acidity. [2] This polymerization fills and occludes blood vessels such as the vasa recta in the kidneys leading to microinfarctions, leakage into surrounding tissues and potentially papillary necrosis and renal infarcts. Renal papillae are especially susceptible to damage eventually causing papillary necrosis since these vessels are only supplied with blood by the vasa recta. [3] The sickling of the cells also contribute to two other mechanisms which are chronic hypoxia and chronic hemolysis. Hypoxia is caused from both the insufficient ability for the red blood cells to transport oxygen alongside blood vessel occlusions promoting the activation of Hypoxia Inducible Factor-1𝛂. [4] The hypoxia also causes the over expression of endothelin-1 and functional nitric oxide deficiency and due to the chronic hemolysis, reactive oxygen species are produced leading to vasoconstriction and further medullary hypoxia. [4] This nitric oxide deficiency alongside endothelin-1 overproduction leads to the inability to properly respond to stress and hemodynamic changes which increases the likelihood of experiencing acute kidney injury. [1]

The hyperfiltration has multiple contributing factors such as the increased cardiac output caused by the normal physiological response to anemia leading to greater renal blood flow and an increase in glomerular filtration rate (GFR). [5] This is not the only factor because having multiple blood transfusions does not reverse this effect. [4] The other contributor is glomerular hypoxia in that it releases local prostaglandins: a potent vasodilator, and nitric oxide synthase which increases renal blood flow and therefore GFR. [4] Hemolysis also plays a role in hyperfiltration through the release of heme oxygenase-1 (HO-1) in response to kidney injury and this enzyme converts heme to biliverdin with the by-product being carbon monoxide. Biliverdin and carbon monoxide both act as antioxidants and carbon monoxide also acts as a vasorelaxant, and this causes an increase in GFR. [4] A consistent increase in GFR can lead to proteinuria, glomerulosclerosis, and can eventually worsen progressive chronic kidney disease (CKD). [2]

Albuminuria is caused by microvascular damage in the kidneys, hemolysis and endothelial dysfunction. From the increased GFR and the ischemic injury caused by the polymerization of sickle cells, scar tissue develops in the glomeruli which reduces the ability of the glomerulus to properly filter proteins leading to proteinuria. [2] The chronic hemolysis causes the release of iron and free hemoglobin in the kidneys. The iron builds up and leaves deposits in the kidneys, and this causes the overproduction of mesangial cells eventually leading to interstitial and glomerular fibrosis. [1] The free plasma hemoglobin contains cytotoxic heme groups which damage renal tubular epithelial cells and the hemoglobin ends up in the filtrate causing hemoglobinuria. [3] Though the hemoglobin can be reabsorbed in the proximal tubules through binding cubilin and megalin, in doing so it competes with albumin, so the build up of hemoglobin in the filtrate reduces albumin resorption which can worsen albuminuria. [3] When it comes to endothelial dysfunction, there is a correlation between soluble FMS-like tyrosine kinase-1 (sFLT-1) and worsening albuminuria. [3] This is because sFLT-1 prevents the binding of vascular endothelial growth factor (VEGF) to a splice variant of its receptor (VEGFR-1) which induces endothelial dysfunction. This as well as other factors that reduce endothelial function such as stress, hypoxia, inflammation, leads to a production of endothelin-1 and this reduces the bioavailability of nitric oxide and releases reactive oxygen species. [6] This induces widening of inter-podocyte radii and lowers the number of podocytes which increases the amount of albumin that is filtered in the glomerulus and worsens albuminuria. [1] The use of endothelin receptor antagonism could have the potential effect to be renally protective. [1]

Presentation

Signs and Symptoms

Microalbuminuria is an early sign of SCN that has a 30-60% of developing in those with sickle cell disease (SCD). [7]

Hematuria can appear in a range of severities from painless and minute to excessive and painful. The presence of visible blood in the urine without pain occurs with a higher frequency in sickle trait than in sickle cell disease and likely results from infarctive episodes in the renal medulla. Despite this condition typically being self-limiting, investigation is recommended because of alternate causes such as renal stones, or medullary carcinoma, especially if bleeding is excessive and if also experiencing flank pain. [2]

Hyposthenuria is the inability for the kidneys to concentrate urine. Functional tubule abnormalities such as nephrogenic diabetes insipidus result from marked reduction in vasa recta blood flow, combined with ischemic tubule injury and sickled erythrocytes in the vasa recta of the inner medulla impairing free water absorption, all causing the production of dilute urine. [2] The concentrating defect also occurs in individuals with sickle trait. This can lead to symptoms such as polyuria and dehydration due to the low water reabsorption. [2]

Increase risk of urinary tract infection from encapsulated bacteria due to hyposplenism from spontaneous infarctions in the spleen (autosplenectomy). Additionally, papillary necrosis can increase the risk of a UTI and all infections should be dealt with promptly to prevent sickle cell crisis. [7]

Initially, hyperfiltration occurs in pediatrics and then after 30 years old, the GFR slowly declines which is proportional to the development of proteinuria. Worsening proteinuria is gradual, but a sudden onset could have a secondary cause such as nephritic syndrome from FSGS or minimal change disease, membranoproliferative glomerulonephritis, or hepatitis C. [7]

Tubular dysfunction, specifically incomplete distal renal tubular acidosis, is caused by the impaired potassium and hydrogen excretion as well as the impaired bicarbonate reabsorption. These contribute to the development of metabolic acidosis, high blood potassium and defects in uric acid excretion which, combined with increased purine synthesis in the bone marrow, results in high blood uric acid levels. [5]

Renal infarcts from total occlusion which can present with pain, vomiting, fever, and high blood pressure. [7]

Complications

Kidney complications of sickle cell disease include cortical infarcts leading to loss of function, persistent bloody urine, and perinephric hematomas. Papillary infarcts, demonstrable radiographically in 50% of patients with sickle trait, lead to an increased risk of bacterial infection in the scarred kidney tissues and functional tubule abnormalities. Other complications include end stage renal disease (ESRD), medullary carcinoma, nephritic syndrome due to concurrent HPV B19 infection (this infection can cause benign self-limiting red cell aplasia). [4]

Risk Factors

Genetic

When looking at SCN, the main contributors leading to either a decrease or increase in CKD progression are the type of hemoglobin inheritance, myosin heavy chain 9, and apolipoprotein L1 genes. In those with the HbSS or HbSβ0 (no normal hemoglobin), they exhibit more severe forms of renal dysfunction at a high occurrence rate compared to those with HbSS or HbSβ+ (reduced number of normal hemoglobin). [4] This ties in with the fetal hemoglobin levels (HbF) in that HbF levels are directly proportional to renal protection, and it has been found that in those with HbSS, a greater than 20% elevation in HbF led to no significant loss in renal function. [4] Alpha-thalassemia has also been found to decrease HbS levels where the co-inheritance of alpha gene deletions reduce red blood cells and hemolysis. [3] This inheritance has been shown to protect against hyposthenuria but the effect on other symptoms are unknown. [3] Specifically in the African American population, the inheritance of an S trait and/or a C trait increases the risk of developing ESRD. [7] For myosin heavy chain 9, and apolipoprotein L1, polymorphisms in these genes can contribute to worsening proteinuria but are not specific towards SCD. [7] Specifically variants in G1 and G2 of apolipoprotein L1 in the African American have shown increased risk of albuminuria, and hyperfiltration. [5]

Environmental

Risk factors for papillary necrosis include analgesics, concomitant cirrhosis, diabetes, pyelonephritis, systemic vasculitis, renal vein thrombosis, and urinary tract obstruction. [3]

Diagnosis

Diagnosis is done through the exclusion of other potential causes. [8] These include acute tubular necrosis from chronic ischemia, membranoproliferative glomerulonephropathy from hepatitis C, nephrolithiasis causing obstructive nephropathy, and papillary necrosis which could be caused by pyelonephritis, diabetes mellitus, or from NSAIDs. [7] The use of renal biopsy is not necessary unless there is a sudden onset of large protein excretions or signs of rapidly declining renal function. [7] Urinalysis, microalbumin to creatinine ratio, quantification of urine protein and ultrasound (to exclude obstructive nephropathy and detect papillary necrosis) are methods used to determine renal function. [7] Early signs include abnormally large and distended glomeruli causing hyperfiltration from as young as two years old. [5] Albuminuria has been used for initial diagnosis in children from as young as four years old but significant damage may have already occurred by the time albuminuria has been detected. [1] Creatinine measurements may not always be accurate because while the glomerulus completely filters creatinine, secondary secretion in the proximal tubules is maximally utilized in those with SCD so GFR may appear to be higher than what it actually is. [1] If exhibiting hematuria, a CT scan should be done to exclude medullary carcinoma and due to multiple blood transfusions, serologies of the autoantibody and complement levels of HIV, hepatitis B and C should also be done. [7] When predicting CKD progression, old age can be a contributor since there is an increase in renal injury and a  decrease in GFR in those over 30 years old. [6] Also albuminuria, GFR, and lactic hydrogenase are used in determining CKD progression. [6] The use of cystatin C may not be clear since while it increases when GFR declines, it has been shown that some people with SCN have similar levels to a healthy individual. [6]

Treatment

Lifestyle

Management of sickle nephropathy is not separate from that of overall patient management. Three-year graft and patient survival in kidney transplant recipients with sickle nephropathy is lower when compared to those with other causes of end-stage kidney disease. [9]

Certain medications should be avoided because of potential damage to the kidneys or can precipitate secondary complications. Nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) should be avoided because of the decrease in renal blood flow causing a decrease in GFR as well as causing hemodynamic injury from glomerular hypertension. [7]

For hematuria, if mild then bed rest and hydration is sufficient to prevent the breakage of clots and to maintain a healthy blood volume, and possibly antibiotics or analgesics if necessary. [4] If severe, then it is recommended to do an ultrasound to see if there is a complication such as renal infarcts or papillary necrosis. [4] At this point the use of epsilon-aminocaproic acid may be recommended to break down clots but its use can increase risk of obstructive nephropathy. [2]

In children, the administration of multiple blood transfusions has been shown to decrease overall kidney damage, but it is unclear how long this effect lasts. [1] Maintaining good hydration is important in those with SCN because of the risk of dehydration from increased urination and there is a major concern of sickle cell crisis that can be prevented with adequate fluid intake. [2]

To manage proteinuria a low protein diet should be avoided because of the decrease in energy and growth in those with SCN but limiting protein to the maximum daily requirement without exceeding it is beneficial in retaining kidney function. [2] A low protein diet may be considered in end stage renal disease (ESRD) alongside phosphate binders, and vitamin D, with the potential of using dialysis or kidney transplants. [2]

Medications

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are beneficial in reducing proteinuria by 50% over a  period of at least six months alongside a slight reduction in GFR but there is an unclear effect in overall CKD progression. [7] If the medication is stopped then the symptoms return to similar levels to what it was before starting the medications. [2] The lowering of nocturia has also been shown most likely from the decrease in GFR. [3] This addition can be done regardless of baseline blood pressure.

Hydroxyurea is an antimetabolite which increases the production of HbF and  decreases HbS synthesis leads to a decrease in HbS polymerization. [5] One of the major concerns in using this medication is myelotoxicity and the development of tolerance over time. [1] No significant effect on GFR but has potential benefit on proteinuria, specifically in the pediatric population. [1] The use of hydroxyurea has been shown to decrease lactic hydrogenase and reticulocytes which is typically used as a predictor for CKD progression since it increases during hemolysis. Since a decrease in hemolysis is correlated with positive SCN outcomes, hydroxyurea may be beneficial in decreasing the risk of SCN complications. [6]

Erythropoietin stimulating agents (ESAs): During normal kidney function in those with SCD, in response to anemia and hypoxia, erythropoietin synthesis is induced, causing increased erythropoietin compared to baseline. Once GFR falls below 60 mL/min, erythropoietin production also declines and it is recommended to add on an ESA to the current therapy; usually at higher doses. [4] The target hemoglobin level should be lower than a normal patient with CKD because of the risk of vaso-occlusive events. [4] Even in ESRD when those with SCD become transfusion dependent, ESAs can still be used to increase the interval between infusions. [4] If using ESAs, it is important to maintain iron levels to maintain the ability to produce red blood cells especially in those with CKD since sub-clinical bleeding is common, and there is decreased iron absorption. IV iron therapy is recommended if not receiving the necessary iron from blood transfusions but the dosing is unclear. [4]

Diuretics are generally not used because of the decrease in blood volume which can cause a person with SCD to have a sickle cell crisis but it can help treat circulatory overload; a condition caused from blood transfusions where there is too much fluid in the circulatory system. [7] Loop diuretics (furosemide) have also been used in treating severe hematuria by increasing urine flow. [7]

Related Research Articles

Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds in the blood. It is largely related to insufficient or dysfunctional filtering of blood by the kidneys. It can lead to uremia and acute kidney injury if not controlled.

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<span class="mw-page-title-main">Nephron</span> Microscopic structural and functional unit of the kidney

The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure called Bowman's capsule. The renal tubule extends from the capsule. The capsule and tubule are connected and are composed of epithelial cells with a lumen. A healthy adult has 1 to 1.5 million nephrons in each kidney. Blood is filtered as it passes through three layers: the endothelial cells of the capillary wall, its basement membrane, and between the foot processes of the podocytes of the lining of the capsule. The tubule has adjacent peritubular capillaries that run between the descending and ascending portions of the tubule. As the fluid from the capsule flows down into the tubule, it is processed by the epithelial cells lining the tubule: water is reabsorbed and substances are exchanged ; first with the interstitial fluid outside the tubules, and then into the plasma in the adjacent peritubular capillaries through the endothelial cells lining that capillary. This process regulates the volume of body fluid as well as levels of many body substances. At the end of the tubule, the remaining fluid—urine—exits: it is composed of water, metabolic waste, and toxins.

<span class="mw-page-title-main">Kidney failure</span> Disease where the kidneys fail to adequately filter waste products from the blood

Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly and can often be irreversible. Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications of acute and chronic failure include uremia, hyperkalaemia, and volume overload. Complications of chronic failure also include heart disease, high blood pressure, and anaemia.

<span class="mw-page-title-main">Nephritis</span> Inflammation of the kidneys

Nephritis is inflammation of the kidneys and may involve the glomeruli, tubules, or interstitial tissue surrounding the glomeruli and tubules. It is one of several different types of nephropathy.

<span class="mw-page-title-main">Juxtaglomerular apparatus</span> Structure that regulates function of each nephron

The juxtaglomerular apparatus is a structure in the kidney that regulates the function of each nephron, the functional units of the kidney. The juxtaglomerular apparatus is named because it is next to (juxta-) the glomerulus.

<span class="mw-page-title-main">Glomerular filtration rate</span> Renal function test

Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Hematuria</span> Medical condition

Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with a microscope or laboratory test. Blood that enters and mixes with the urine can come from any location within the urinary system, including the kidney, ureter, urinary bladder, urethra, and in men, the prostate. Common causes of hematuria include urinary tract infection (UTI), kidney stones, viral illness, trauma, bladder cancer, and exercise. These causes are grouped into glomerular and non-glomerular causes, depending on the involvement of the glomerulus of the kidney. But not all red urine is hematuria. Other substances such as certain medications and foods can cause urine to appear red. Menstruation in women may also cause the appearance of hematuria and may result in a positive urine dipstick test for hematuria. A urine dipstick test may also give an incorrect positive result for hematuria if there are other substances in the urine such as myoglobin, a protein excreted into urine during rhabdomyolysis. A positive urine dipstick test should be confirmed with microscopy, where hematuria is defined by three or more red blood cells per high power field. When hematuria is detected, a thorough history and physical examination with appropriate further evaluation can help determine the underlying cause.

<span class="mw-page-title-main">Renal medulla</span> Innermost part of the kidney

The renal medulla is the innermost part of the kidney. The renal medulla is split up into a number of sections, known as the renal pyramids. Blood enters into the kidney via the renal artery, which then splits up to form the segmental arteries which then branch to form interlobar arteries. The interlobar arteries each in turn branch into arcuate arteries, which in turn branch to form interlobular arteries, and these finally reach the glomeruli. At the glomerulus the blood reaches a highly disfavourable pressure gradient and a large exchange surface area, which forces the serum portion of the blood out of the vessel and into the renal tubules. Flow continues through the renal tubules, including the proximal tubule, the loop of Henle, through the distal tubule and finally leaves the kidney by means of the collecting duct, leading to the renal pelvis, the dilated portion of the ureter.

<span class="mw-page-title-main">Assessment of kidney function</span> Ways of assessing the function of the kidneys

Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.

<span class="mw-page-title-main">Kidney disease</span> Damage to or disease of a kidney

Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.

<span class="mw-page-title-main">Glomerulus (kidney)</span> Functional unit of nephron

The glomerulus is a network of small blood vessels (capillaries) known as a tuft, located at the beginning of a nephron in the kidney. Each of the two kidneys contains about one million nephrons. The tuft is structurally supported by the mesangium, composed of intraglomerular mesangial cells. The blood is filtered across the capillary walls of this tuft through the glomerular filtration barrier, which yields its filtrate of water and soluble substances to a cup-like sac known as Bowman's capsule. The filtrate then enters the renal tubule of the nephron.

<span class="mw-page-title-main">Chronic kidney disease</span> Medical condition

Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include high blood pressure, bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization.

<span class="mw-page-title-main">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Hypertensive kidney disease</span> Medical condition

Hypertensive kidney disease is a medical condition referring to damage to the kidney due to chronic high blood pressure. It manifests as hypertensive nephrosclerosis. It should be distinguished from renovascular hypertension, which is a form of secondary hypertension, and thus has opposite direction of causation.

<span class="mw-page-title-main">Sickle cell trait</span> Medical condition

Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene, but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele. Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin.

Phosphate nephropathy or nephrocalcinosis is an adverse renal condition that arises with a formation of phosphate crystals within the kidney's tubules. This renal insufficiency is associated with the use of oral sodium phosphate (OSP) such as C.B. Fleet's Phospho soda and Salix's Visocol, for bowel cleansing prior to a colonoscopy.   

<span class="mw-page-title-main">Analgesic nephropathy</span> Medical condition

Analgesic nephropathy is injury to the kidneys caused by analgesic medications such as aspirin, bucetin, phenacetin, and paracetamol. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication.

<span class="mw-page-title-main">Renal papillary necrosis</span> Medical condition

Renal papillary necrosis is a form of nephropathy involving the necrosis of the renal papilla. Lesions that characterize renal papillary necrosis come from an impairment of the blood supply and from subsequent ischemic necrosis that is diffuse.

References

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