Sickle cell nephropathy is a type of kidney disease 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 slower 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.

In younger patients, the disease is characterized by renal hyperperfusion, glomerular hypertrophy, and glomerular hyperfiltration. Some 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 __TOC__

Pathophysiology The development of sickle cell nephropathy (SCN) typically occurs in childhood as seen in the appearance of hyperfiltration and proteinuria. 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. 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. 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. 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. 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.

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). This is not the only factor because having multiple blood transfusions does not reverse this effect. 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. 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. A consistent increase in GFR can lead to proteinuria, glomerulosclerosis, and can eventually worsen progressive chronic kidney disease (CKD).

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. 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. The free plasma hemoglobin contains cytotoxic heme groups which damage renal tubular epithelial cells and the hemoglobin ends up in the filtrate causing hemoglobinuria. 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. When it comes to endothelial dysfunction, there is a correlation between soluble FMS-like tyrosine kinase-1 (sFLT-1) and worsening albuminuria. 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. 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. The use of endothelin receptor antagonism could have the potential effect to be renally protective.

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).

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.

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. 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.

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.

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.

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.

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

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).

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). 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. Alpha-thalassemia has also been found to decrease HbS levels where the co-inheritance of alpha gene deletions reduce red blood cells and hemolysis. This inheritance has been shown to protect against hyposthenuria but the effect on other symptoms are unknown. Specifically in the African American population, the inheritance of an S trait and/or a C trait increases the risk of developing ESRD. For myosin heavy chain 9, and apolipoprotein L1, polymorphisms in these genes can contribute to worsening proteinuria but are not specific towards SCD. Specifically variants in G1 and G2 of apolipoprotein L1 in the African American have shown increased risk of albuminuria, and hyperfiltration.

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

Diagnosis