Renal Complications in Hemoglobinopathies Miguel R Abboud M

Renal Complications in Hemoglobinopathies Miguel R. Abboud M. D. Department of Pediatrics and Adolescent Medicine American University of Beirut Medical Center

Sickle Cell Disease: Overview • Sickle cell disease (SCD) is one of the most common severe monogenic disorders in the world. • Despite a simple molecular etiology, SCD is a multisystem disease, associated with episodes of acute illness and progressive organ damage.

Sickle Nephropathy • Renal involvement in SCD includes a variety of glomerular and tubular disorders and is associated with increased mortality if left untreated. • Kidneys can be affected in both patients with sickle cell disease and even in sickle cell trait. • Kidney disease begins in childhood and progresses into adulthood in patients with SCD. Abbott KC, Hypolite IO, Agodoa LY. Sickle cell nephropathy at end-stage renal disease in the United States: patient characteristics and survival. Clin Nephrol. 2002; 58: 9 -15.

Overview Improved care and therapies for SCD Longer lifespan Increased endorgan damage including CKD Not all renal disease or renal failure in SCD is due to SCN. Other medical conditions like lupus nephritis, HCV, HIV nephropathy and others must be ruled-out. Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

SC Kidney Disease Adults with SCA 40% microalbuminuria 20 -30% proteinuria The mean survival after developing ESRD is 4 years, and 40% of SCA patients will die within 20 months of starting dialysis. 4 -18% ESRD needing dialysis or transplant Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4 -decade observational study of 1056 patients. Med Baltim. 2005; 84: 363– 376. Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991; 115: 614– 620.

The microvasculature of the nephron. Nangaku M JASN 2006; 17: 17 -25 © 2006

Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Distal nephron (hyposthenuria, impaired acidification) Proximal tubule (B 2 MG, Po 4, uric acid, creatinine secretion) Hematuria and papillary necrosis Renal abnormalities in SCD Hemodynamic changes (GFR, RBF) Glomerulus (proteinuria, NS, CRF)

Modified hemolysis-endothelial dysfunction phenotype and proposed renal pathophysiology in human SCD. Hemolysis in human SCD leads to NO scavenging by plasma hemoglobin (Hb. SS) and increased amounts of heme because of the instability of sickle hemoglobin. Nath K A , Katusic Z S JASN 2012; 23: 781 -784 © 2012 by American Society of Nephrology

Classification Based on Phenotypes Cortex: hemolysis-endothelial dysfunction phenotype Hyperfiltration Glomerular hypertrophy Glomerulopathy Hypermetabolism CKD Medulla: viscosity-vasoocclusion phenotype Hematuria Papillary necrosis Impaired concentrating ability Impaired potassium excretion Tubular acidosis Nath KA, Katusic ZS. Vasculature and kidney complications in sickle cell disease. J Am Soc Nephrol. 2012; 23: 781784.

Classification Based on Phenotypes • Microalbuminuria and hyperfiltration are more associated with hemolytic phenotype of SCD spectrum. Haymann JP, Stankovic K, Levy P, et al. Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Clin J Am Soc Nephrol. 2010; 5: 756– 761. • In the hemolysis-endolthelial dysfunction type, in addition to the intermittent, localized microvascular occlusion, kidney pathology is also caused by multi-organ vasculopathy related to the chronic nitric oxide depletion from the ongoing hemolysis Kato GJ, Wang Z, Machado RF, Blackwelder WC, Taylor JG 6 th, Hazen SL. Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death. Br J Haematol. 2009; 145(4): 506 -13.

Urine concentration abnormalities • Following overnight water deprivation, urine osmolality is significantly lower in subjects with SCA compared to normal controls. RBC Sickling Medullary congestion and fibrosis Loss of gradient Impaired Na reabsorption by collecting ducts Scheinman JI. Sickle cell disease and the kidney. Nat Clin Pract Nephrol. 2009; 5: 78– 88. Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26: 2099– 2109.

Urine concentration abnormalities • The inability to concentrate urine to its maximum (hyposthenuria) as a response to water deprivation is an early finding in sickle cell nephropathy. • It has been observed in infants at 6– 12 months of age. • Hyposthenuria is the most common tubular dysfunction in SCD and can be found in patients with sickle cell trait. • Severity is associated with Hb. S levels. • Patients with higher levels of Hb. F have a greater ability to concentrate urine. Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am J Hematol. 2002; 63: 205– 211. Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371 -1379.

Urine concentration abnormalities • Symptoms – May be asymptomatic in absence of water deprivation – Polyuria secondary to polydipsia – Nocturnal enuresis, reported in 28% to 37% of children with SCD Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371 -1379. Bruno D, Wigfall DR, Zimmerman SA, Rosoff PM, Wiener JS. Genitourinary complications of sickle cell disease. J Urol 2001; 166: 803– 811.

Urinary Acidification Deficit Medullary ischemia in SCD Impaired urinary acidification (energy-dependent process that necessitates a high proton gradient) Incomplete form of RTA type IV with hyperchloremic hyperkalemic metabolic acidosis • • Less frequent than the concentration deficit More problematic in patients with worsening renal fuction Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am J Hematol. 2002; 63: 205– 211. Batlle, D. , Itsarayoungyuen, K. , Arruda, J. A. & Kurtzman, N. A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. American Journal of Medicine. 1982; 72, 188– 192.

Increased Proximal Tubule Function • The increase in sodium and water loss from the collecting ducts leads to a reactive increase in sodium and water reabsorption by the proximal tubule. • Sodium reabsorption is the driving force for the reabsorption of other solutes: – – β 2 -microglobulin Phosphate hyperphosphatemia Uric acid Creatinine • Up to 30% of the total creatinine excretion can arise from tubular secretion, so creatinine-based measurements of GFR can significantly overestimate renal function. Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Hyperfiltration • An increase in renal blood flow and glomerular filtration is frequently observed in SCD, becoming apparent around 1 year after birth and tending to decrease with aging. It is involved in the pathogenesis of glomerular disease and kidney failure in SCD. • BABY HUG Trial: – At a mean age of 13 months, the mean serum creatinine and serum cystatin in patients with SCD were similar to published age norms. – However, isotope-derived measurement of GFR showed that these patients had significantly elevated GFR compared with the age norm at 1 year of age. These results were statistically significant (P-value <0. 001). Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer. 2012; 59(4): 668 -74.

Hyperfiltration Aygun B, Mortier NA, Smeltzer MP, Hankins JS, Ware RE. Glomerular hyperfiltration and albuminuria in children with sickle cell anemia. Pediatr Nephrol. 2011; 26(8): 1285– 1290.

Hyperfiltration Current theory Medullary ischemia and vasa recta destruction Production of vasodilating substances (PGs, NO) Increased renal blood flow Increased glomerular size, and glomerulosclerosis later Increased GFR Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26: 2099– 2109.

Glomerular Hypertrophy Wesson DE. The initiation and progression of sickle cell nephropathy. Kidney Int. 2002; 61: 2277– 2286.

Hyperfiltration • The renal kinin-kallikrein system also seems to be involved in hyperfiltration, as the production of bradykinins can contribute to vasodilation and glomerular blood flow increase. • Bergmann et al(2006): The urinary excretion of kallikrein showed a significant correlation with albuminuria. • Further studies are needed. Bergmann S, Zheng D, Barredo J, Abboud MR, Jaffa AA. Renal kallikrein: a risk marker for nephropathy in children with sickle cell disease. J Pediatr Hematol Oncol. 2006; 28(3): 147 -53.

Hyperfiltration • Haem oxygenase-1 (HO-1) has been shown to be upregulated in injured tissues including the kidneys in response to the ongoing hemolysis in SCD. • HO-1 is responsible for the conversion of heme to biliverdin with the subsequent release of carbon monoxide (CO). Both biliverdin and CO are potent antioxidants and the CO acts locally as a vasorelaxant thus increasing renal blood flow and GFR. Nath KA. Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney International. 2006; 70, 432– 443.

Microalbuminuria and Proteinuria • Increased urine albumin levels is an early manifestation of SCN. • It may start in late childhood and tends to increase with age as the kidney sustains more damage over time. • Data by Sharpe & Thein: SCD Patients Age Group Proportion with urinary albumin: creatinine ≥ 4. 5 mg/mmol 15 -23 years 30% 23 -35 years 40% >35 years 60% Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Microalbuminuria and Proteinuria • Risk factors: – Advanced age (shown in almost all studies) – Low hemoglobin (shown in some studies) • No significant association between proteinuria and other SCD complications like ACS, VOCs, ASS, etc. Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26: 2099– 2109. • No difference in WBC, platelet count, reticulocyte count, LDH levels in patients with microalbuminuria vs. normoalbuminuria Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006; 17: 2228– 2235.

Microalbuminuria and Proteinuria • Nephrotic syndrome is rare poor renal prognosis • Hypothesis of 5 clinical stages (further longitudinal studies needed): Normoalbuminuria Microalbuminuria Macroalbuminuria with preserved GFR Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006; 17: 2228– 2235. Macroalbuminuria with progressive renal insufficiency ESRD

Microalbuminuria and Proteinuria • A rare reported cause of acute nephrotic syndrome in SCD is human parvovirus B 19 infection. • HPV B 19 infection often causes aplastic crisis in SCD, and in some reports this acute infection was followed by acute nephrotic syndrome within 2– 3 months. • Older SCD patients with acute HPV B 19 infection may be more susceptible to complications, including the development of nephrotic syndrome and progressive renal fibrosis. Quek L, Sharpe C, Dutt N, et al. Acute human parvovirus B 19 infection and nephrotic syndrome in patients with sickle cell disease. Br J Haematol. 2010; 149(2): 289 -91.

Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Hematuria • One of the most frequent complications of sickle cell nephropathy • It is usually macroscopic and painless, but can also be microscopic and/or painful • Most frequent renal abnormality in patients with sickle cell trait • Hematuria can originate in one or both kidneys as a result of papillary necrosis or microthrombosis in peritubular capillaries, and it is also associated with infections or late transfusion reactions Schneinman JI. Sickle cell disease and the kidney. Nat Clin Pract Nephrol. 2009; 5: 78– 88. Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371 -1379.

Hematuria • It is usually self-limited and managed by good hydration, pain medications and antibiotics when needed • The etiology of renal papillary necrosis (RPN) includes diabetes, analgesic abuse or overuse, sickle cell disease, pyelonephritis, renal vein thrombosis, tuberculosis, and obstructive uropathy. RPN can be found incidentally on imaging in asymptomatic patients. • More severe causes of hematuria should be investigated like renal stones, or carcinomas in older populations. Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Acute Renal Failure • ARF is less common than CKD in patients with SCD • Most commonly due to dehydration, as a result of urinary concentration deficit after water deprivation • Complete recovery of renal function occurs with adequate treatment • Can also result from sepsis, heart failure, renal vein thrombosis, rhabdomyolysis, hepato-renal syndrome, multiple-organ failure Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371 -1379.

Chronic Kidney Disease • Some patients with proteinuria progress to CKD • 25 -year prospective cohort study including 725 patients with SCD (Hb. SS): – 4. 2% developed chronic renal failure (RF) – RF was preceded by ineffective erythropoiesis with decreasing Hb, proteinuria, nephrotic syndrome, hypertension and microscopic hematuria – Chronic restrictive lung disease, leg ulcers and stroke were 3 times more common in these patients Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991; 115: 614– 620.

Chronic Kidney Disease Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991; 115: 614– 620.

Chronic Kidney Disease • Generally diagnosed between 30 and 40 years of age • Guasch et al: Renal insufficiency (GFR < 90 ml/min) Hb SS disease Other sickling hemoglobinopathies 21% 27% Advanced CKD stage 29% III 6% Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006; 17: 2228– 2235.

Chronic Kidney Disease • Based on the results of a 4 -decade observational study by Powars et al: SCD Subtype Median age of onset of renal failure Hb SS 23 -37 years Hb SC 50 years Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4 -decade observational study of 1056 patients. Med Baltim. 2005; 84: 363– 376. Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991; 115: 614– 620.

Other GU Abnormalities • Cases of testicular infarction described in patients with SCD or even sickle cell trait. • Renal medullary carcinoma, a rare aggressive tumor of the kidney, has been reported in patients with sickle cell trait, and rarely SCD. Davir CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995; 19: 1– 11.

Renal medullary carcinoma in 11 -year-old boy with known sickle cell trait who presented with 2 -week history of fever, malaise, and weight loss. Dyer R et al. Radiology 2008; 247: 331 -343 © 2008 by Radiological Society of North America

Urinary Tract Infections • Higher risk of UTI than the general population. • Renal papillary necrosis is a risk factor for UTI. • Most frequent pathogens are Escherichia coli, Klebsiella and Enterobacter sp. • Patients are at risk of sepsis, need for prolonged antibiotic treatment. Da Silva GB Jr, Libório AB, De Francesco Daher E. New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol. 2011; 90: 1371 -1379.

Diagnosis • The laboratory findings SCN may include: lower density urine, proteinuria, hematuria, micro- and macroalbuminuria and increased creatinine clearance. • Hyponatremia, hyperkalemia and hypoalbuminemia can be also found. • Serum creatinine levels are low in SCD due to increased urinary excretion, and levels only rise when renal damage is extensive. • Similarly, GFR only decreases in the late stages of SCN. • Creatinine clearance is not a good test to evaluate renal function in SCD as it may overestimate GFR. Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early detection of sickle nephropathy. Am J Hematol 86: 559– 566

Diagnosis • Study by Sundaram et al. comparing characteristics of SCA patients with normoalbuminuria, microalbuminuria and macroalbuminuria • No significant differences in: • Hemoglobin, reticulocyte count and bilirubin (as markers of hemolysis) • WBC counts (inflammation marker) • BP, Cr, BUN, specific gravity • Routine renal indicators do not predict the onset of SCN Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early detection of sickle nephropathy. Am J Hematol 86: 559– 566

Diagnosis • Cystatin C: endogenously produced molecule that is freely filtered in the glomeruli, completely absorbed and broken down by proximal tubular cells. • The plasma concentration increases with reduction in GFR, even in patients with normal creatinine levels. • Estimations of GFR based on serum cystatin C correlate well with isotopically-measured GFR and with the degree of proteinuria. • It is a more accurate surrogate marker of renal function in both adults and children with SCD and can detect early decline in renal function. Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Diagnosis • Other early biomarkers: – Urinary endothelin-1 (ET-1) – Urine kidney injury molecule-1 (KIM-1) – Urinary N-acetyl-b-D-glucosaminidase (NAG) • More studies are required to establish the best method for renal function evaluation. • Combination of more than one biomarker improves diagnostic accuracy.

Diagnosis • Imaging examinations may show caliceal cysts, papillary necrosis, and cortical sclerosis. • Images are usually normal in children. • Increased kidney size can be found in young adults with SCD, whereas among adults older than 40 years, kidney size can be diminished or even atrophic. • Doppler ultrasound changes can be used as early markers. • Renal biopsy should be considered in cases of significant proteinuria, when glomerular diseases are suspected and in the cases of rapid or unexplained renal function loss. • In the cases of isolated hematuria in SCD, renal biopsy is not indicated. De Jong PE, Statius van Eps LW. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int. 1985; 27: 711– 717.

Treatment • There are no established guidelines for treatment of sickle cell nephropathy. • Data from case series and extrapolation from renal disease due to other causes such as diabetic nephropathy.

Treatment Transfusions • Alvarez et al (2006): Chronic transfusions started before the age of 9 years may protect against microalbuminuria. • Becton et al (2010): no correlation between microalbuminuria and transfusions. • No sufficient evidence for use of transfusions for prevention or treatment of SCN. lvarez O, Montane B, Lopez G, Wilkinson J, Miller T. Early blood transfusions protect against microalbuminuria in children with sickle cell disease. Pediatr Blood Cancer. 2006; 47(1): 71– 76. Becton LJ, Kalpatthi RV, Rackoff E, et al. Prevalence and clinical correlates of microalbuminuria in children with sickle cell disease. Pediatr Nephrol. 2010; 25, 1505– 1511.

Treatment Hydroxyurea • Data from the BABY HUG trial • Children who received hydroxyurea had: – Better urine concentrating capacity than children on placebo – Smaller kidney volumes on ultrasound than those on placebo • However, hydroxyurea had no effect on GFR. Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer. 2012; 59(4): 668 -74.

Treatment HSCT • Most studies exclude SCD patients with established renal disease from receiving HSCT. • Study by Hsieh et al (2009): – HCT in 10 adults with SCD included 3 patients with renal dysfunction – After an average of 30 months of follow up: the decline in renal function post-procedure did not exceed the slope before the transplantation. • Some reports describe HCT as a safe procedure in adults with ESRD, suggesting that the presence of advanced SCN should not exclude patients from receiving this treatment if available. Hsieh MM, Kang EM. Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009; 361(24): 2309– 2317.

Treatment ACE Inhibitors • ACE inhibitors have been used in small studies and showed decrease in proteinuria and hyperfiltration. • Risk of developing hyperkalemia. • No data on the use of ACEI in children with SCN. Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Treatment Advanced CKD • Patients with ESRD secondary to SCN have poor prognosis. • Better survival after renal transplantation has been shown in some studies. • More data is needed. Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3): 287 -297.

Renal disease in thalassemia

Overview • Thalassemia patients suffer from end-organ damage; however, little is known about the mechanisms and treatment of kidney involvement. • Most studies available are cross-sectional and involve a small number of patients. • Proper assessment of renal function abnormalities in thalassaemia can be challenging because of the increased use of iron chelators, which themselves can also affect renal function. Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta thalassaemia. Blood Rev. 2010; 24: 239– 244.

Mechanisms of renal disease in β-thalassaemia intermedia Glomerular filtration rate (GFR) Chronic anaemia/hypoxia Iron overload Iron chelation ? ● ● ● ● ● Vascular resistance Renal plasma flow GFR ● ● ● Endothelial and epithelial damage Transudation of macromolecules Mesangial dysfunction GFR ● ● Tubular cell damage Epithelial-mesenchymal transdifferentiation Tubulointerstitial injury Glomerular sclerosis GFR ● ● Relative iron depletion Abnormal mitochondrial function and arachidonic acid cascade Tubuloglomerular feedback and haemodynamic change GFR Tubular cells Chronic anaemia/hypoxia ● ● ● Iron overload Oxidative stress Lipid peroxidation Cellular damage Iron chelation ● Nephrotoxicity Musallam KM, Taher AT. J Am Soc Nephrol. 2012. In press.

Renal impairment in β-thalassaemia intermedia ● 50 β-TI patients ● e. GFR – median 142. 3 ml/min/1. 73 m 2 – glomerular hyperfiltration in 24 (48%) – negative correlation between e. GFR and age ● UPr/UCr ratio – median 213. 3 mg/g – proteinuria (UPr/UCr ratio > 500 mg/g) in 7 (14%) – proteinuria associated with elevated LIC (> 7 mg Fe/g dry wt), NTBI levels, and nucleated RBC counts e. GFR = estimated glomerular filtration rate; NTBI = non-transferrin-bound iron; UPr/UCr = urinary protein to creatinine. e. GFR (m. L/min/1. 73 m 2) – median age 28 years 300 200 180 160 140 120 100 80 60 40 20 0 R 2: 0. 413; p < 0. 001 Beta: − 1. 60 (95% CI: − 2. 15 to − 1. 05) Constant: 189. 59 (95% CI: 1730. 07 to 206. 12) 0 10 20 30 40 50 60 70 Age (years) Ziaydef F Mussalam KM, et al Kid Int in lress.

Tubular Abnormalities • Study on 94 patients with TM: Koliakos G, Papachristou F, Koussi A, et al. Urine biochemical markers of early renal dysfunction are associated with iron overload in beta-thalassaemia. Clin Lab Haematol. 2003; 25: 105– 9.

Tubular Abnormalities Study by Sumboonnanonda et al. on 104 TM patients: – Aminoaciduria in onethird of the patients – Low molecular weight proteinuria in all patients Study of 166 TM patients: Finding % Hypercalciuria 12. 9 Hyperphosphaturia 9. 2 Hypermagnesuria 8. 6 Hyperuricosuria 36 Increased β 2 microglobulin excretion 13. 5 Sadeghi-Bojd S, Hashemi M, Karimi M. Renal tubular function in patients with beta-thalassaemia major in Zahedan, southeast Iran. Singapore Med J. 2008; 49: 410– 2. Sumboonnanonda A, Malasit P, Tanphaichitr VS, Ong-ajyooth S, Sunthornchart S, Pattanakitsakul S, et al. Renal tubular function in beta-thalassemia. Pediatr Nephrol 1998; 12: 280– 3.

Tubular Abnormalities In patients with TM and TI, direct correlation of renal function disturbance to total amount of transfused iron, but not to the actual ferritin level. Smolkin V, Halevy R, Levin C, et al. Renal function in children with beta-thalassemia major and thalassemia intermedia. Pediatr Nephrol. 2008; 23: 1847– 51.

Tubular Abnormalities • Toxicity of iron overload • • Hemosiderin deposits on autopsy in patients with TM Correlation between ferritin levels and markers of kidney injury Oxidative stress and lipid peroxidation in renal tubules Reversal of tubular defects after starting iron chelation • Toxicity of anemia • Oxidative stress and lipid peroxidation • Damage secondary to hypoxia Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta thalassaemia. Blood Rev. 2010; 24: 239– 244.

Parameters After HSCT Sumboonnanonda A, Sanpakit K, Piyaphanee N. Renal tubule function in betathalassemia after hematopoietic stem cell transplantation. Pediatr Nephrol. 2009; 24: 183– 7.

GFR Abnormalities Among regularly transfused patients, creatinine clearance was lower in adults than children. Decrease in Cr clearance with blood transfusions may be related to alleviation from anemia. Quinn CT, Johnson VL, Kim HY, et al. Renal dysfunction in patients with thalassaemia. Br J Haematol. 2011; 153: 111 -117.

GFR Abnormalities Anemia Injury and transudation of molecules Mesangial overload and dysfunction Decreased SVR Stretching of the glomerular capillary wall Progressive decline in GFR, worsened by iron overload Hyperdynamic circulation Increased RBF and hyperfiltration Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta thalassaemia. Blood Rev. 2010; 24: 239– 244.

Multiple mechanisms of chronic hypoxia in the kidney. Nangaku M JASN 2006; 17: 17

GFR Abnormalities • Study by Ali et al. (Iran) TM (50 patients) TI (50 patients) Mean Hb (g/d. L) 9. 11 ± 0. 83 9. 81 ± 1. 13 Mean ferritin level (mcg/L) 3533 ± 201 871 ± 82 Mean serum creatinine (mcmol/L) 78. 7 ± 17. 7 52. 2 ± 32. 7 Ali D, Mehran K, Moghaddam AG. Comparative evaluation of renal findings in Beta-thalassemia major and intermedia. Saudi J Kidney Dis Transpl. 2008; 19: 206– 9.

Iron Chelators • Cases of acute renal failure (ARF) attributed to deferoxamine overdose have been reported. • Damage was reversible, and renal biopsy in one patient showed renal tubular necrosis. • ARF also described in patients on oral deferasirox (Exjade) who had: – Advanced age – High-risk myelodysplastic syndromes – Underlying renal/hepatic problems Musallam KM, Taher AT. Mechanisms of renal disease in β-thalassemia. J Am Soc Nephrol. 2012; 23(8): 1299 -302.

Iron Chelators • Mild dose-dependent increases in creatinine were reported in patients on deferoxamine or deferasirox. • Transient changes, not exceeding twice the upper limit of normal. Some spontaneously normalized, others required dose-reduction. • Creatinine increases were not progressive over a 5 -year follow -up. • Increases in serum creatinine were more often observed in patients with lower ferritin levels, less frequent blood transfusions, and lower LIC. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL 670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006; 107: 3455– 62.

Iron Chelators Current theory Relative iron depletion 1. Damage to mitochondrial function in tubular cells. 2. Interference with arachidonic acid cascade 1. Tubuloglomerular feedback, decrease in GFR 2. Imbalance in prostaglandins, decrease in GFR Musallam KM, Taher AT. Mechanisms of renal disease in β-thalassemia. J Am Soc Nephrol. 2012; 23(8): 1299 -302.

Nephropathy in Thalassemias • Data is still lacking. • More long-term studies involving a larger number of patients with thalassemia major and intermedia are needed.

• Questions

De Jong PE, Statius van Eps LW. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int. 1985; 27: 711– 717.

Urine concentration abnormalities • Unrelated to ADH production • Study by Tharaux et al: – Endothelin-1 (ET-1) counters the effects of ADH on tubular functions – SCD patients at steady state have marked increase in urinary ET-1 excretion, which is likely to favor diabetes insipidus and subsequent dehydration Tharaux PL, Hagege I, Placier S, et al. Urinary endothelin-1 as a marker of renal damage in sickle cell disease. Nephrol Dial Transplant. 2005; 20: 2408– 2413

Hyperfiltration Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26: 2099– 2109.

Age and the prevalence of albuminuria in adults with sickle cell hemoglobinopathies. □, normoalbuminuria; □, microalbuminuria; ▪, macroalbuminuria. Guasch A et al. JASN 2006; 17: 2228 -2235 © 2006 by American Society of Nephrology

Microalbuminuria and Proteinuria Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26: 2099– 2109.

Figure 1. Intrarenal arterial anatomy. Jung D C et al. Radiographics 2006; 26: 1827

Diagnosis Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early detection of sickle nephropathy. Am J Hematol 86: 559– 566

Plasma concentration of endothelin-1 on day 0 and day 1, after overnight water deprivation, in 17 sickle cell patients at steady state and 17 matched controls. Tharaux P et al. Nephrol. Dial. Transplant. 2005; 20: 24082413 © The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals. permissions@oxfordjournals. org

Distribution of ET-1 urinary output for three hours on day 1 (x) and urinary albumin output normalized against creatinine (y) in the study sample of SCD patients, and the corresponding estimated linear regression equation (P<0. 01, Spearman's non-parametric correlation test). Tharaux P et al. Nephrol. Dial. Transplant. 2005; 20: 24082413 © The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals. permissions@oxfordjournals. org

NAG KIM-1 Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early detection of sickle nephropathy. Am J Hematol 86: 559– 566

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