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

2. 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.

3. 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.

4. Overview Improved care and therapies for SCD Longer lifespan
Increased end-organ 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):

5. 4-18% ESRD needing dialysis or transplant
SC Kidney Disease
Adults with SCA
40% microalbuminuria
20-30% proteinuria
4-18% ESRD needing dialysis or transplant
The mean survival after developing ESRD is 4 years, and 40% of SCA patients will die within 20 months of starting dialysis.
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.

6. The microvasculature of the nephron.
The microvasculature of the nephron. The peritubular capillary plexus is fed by glomerular efferent arterioles and supplies nutrients and oxygen to tubular and interstitial cells. Illustration by Josh Gramling—Gramling Medical Illustrations.
Nangaku M JASN 2006;17:17-25
©2006 by American Society of Nephrology

7. A representation of the renal nephron demonstrating the regions damaged in sickle cell disease leading to the clinical manifestations of sickle cell nephropathy
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3):

8. Renal abnormalities in SCD
Distal nephron (hyposthenuria, impaired acidification)
Hemodynamic changes (GFR, RBF)
Glomerulus (proteinuria, NS, CRF)
Hematuria and papillary necrosis
Proximal tubule (B2MG, Po4, uric acid, creatinine secretion)
Reference??

9. Modified hemolysis-endothelial dysfunction phenotype and proposed renal pathophysiology in human SCD. Hemolysis in human SCD leads to NO scavenging by plasma hemoglobin (HbSS) and increased amounts of heme because of the instability of sickle hemoglobin.
Modified hemolysis-endothelial dysfunction phenotype and proposed renal pathophysiology in human SCD. Hemolysis in human SCD leads to NO scavenging by plasma hemoglobin (HbSS) and increased amounts of heme because of the instability of sickle hemoglobin. Heme is cytotoxic, thereby injuring glomerular cells and causing proteinuria and CKD. Induction of heme oxygenase-1, through the generation of carbon monoxide and other actions, induces vasodilation, and thus promotes hyperfiltration. The minus sign signifies that induction of heme oxygenase-1 can mitigate the adverse effects of heme by degrading heme and other cytoprotective effects of heme oxygenase-1.
Nath K A , Katusic Z S JASN 2012;23:
©2012 by American Society of Nephrology

10. 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:

11. Classification Based on Phenotypes
Microalbuminuria and hyperfiltration are more associated with hemolytic phenotype of SCD spectrum.
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
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.
Kato GJ, Wang Z, Machado RF, Blackwelder WC, Taylor JG 6th, 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):

12. 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.

13. 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 HbS levels.
Patients with higher levels of HbF 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:

14. 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:
Bruno D, Wigfall DR, Zimmerman SA, Rosoff PM, Wiener JS. Genitourinary complications of sickle cell disease. J Urol 2001;166: 803–811.

15. 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.

16. 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:
β2-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):

17. 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):

18. Hyperfiltration
Glomerular filtration rate by age group. The measured DTPA GFR values are illustrated in standard box-and-whisker plots. Group means are marked with a cross and connected with a line. The number of patients in each age group is shown in parentheses.
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.

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

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

21. 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):

22. 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.

23. 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):

24. 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.
No difference in WBC, platelet count, reticulocyte count, LDH levels in patients with microalbuminuria vs. normoalbuminuria
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.
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.

25. 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
Macroalbuminuria with progressive renal insufficiency
ESRD
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.

26. Microalbuminuria and Proteinuria
A rare reported cause of acute nephrotic syndrome in SCD is human parvovirus B19 infection.
HPV B19 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 B19 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 B19 infection and nephrotic syndrome in patients with sickle cell disease. Br J Haematol. 2010; 149(2):

27. Histology of acute sickle nephropathy in a kidney transplant
Histology of acute sickle nephropathy in a kidney transplant. (A and B) Sickled red blood cells (RBCs) within the capillaries of the glomerulus. (C) Sickled RBCs within peritubular capillaries. (D) An electron micrograph of a capillary occluded with sickled RBCs.
Sharpe CC, Thein SL. Sicke cell nephropathy – a practical approach. Br J Haematol. 2011; 155(3):

28. 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:

29. 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):

30. 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:

31. Chronic Kidney Disease
Some patients with proteinuria progress to CKD
25-year prospective cohort study including 725 patients with SCD (HbSS):
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.

32. 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.

33. Chronic Kidney Disease
Generally diagnosed between 30 and 40 years of age
Guasch et al:
Hb SS disease
Other sickling hemoglobinopathies
Renal insufficiency (GFR < 90ml/min)
21%
27%
Advanced CKD stage III
29% 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.

34. 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.

35. 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.

36. 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.
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. (a) Reconstructed coronal contrast-enhanced corticomedullary-phase CT image reveals bean-type mass replacing lower two-thirds of the left kidney. Renal contour is undisturbed. (b) Reconstructed coronal contrast-enhanced corticomedullary-phase CT image obtained at a more ventral level reveals extensive left paraaortic lymphadenopathy (arrows). Diagnosis of RMC was confirmed at surgery. (Reprinted, with permission, from reference 25.)‏
Dyer R et al. Radiology 2008;247:
©2008 by Radiological Society of North America

37. 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.
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. (a) Reconstructed coronal contrast-enhanced corticomedullary-phase CT image reveals bean-type mass replacing lower two-thirds of the left kidney. Renal contour is undisturbed. (b) Reconstructed coronal contrast-enhanced corticomedullary-phase CT image obtained at a more ventral level reveals extensive left paraaortic lymphadenopathy (arrows). Diagnosis of RMC was confirmed at surgery. (Reprinted, with permission, from reference 25.)‏
Dyer R et al. Radiology 2008;247:
©2008 by Radiological Society of North America

38. 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:

39. 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

40. 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

41. 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):

42. 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.
New insights

43. 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.

44. 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.

45. 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.

46. 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):

47. 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.

48. 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):

49. 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):

50. Renal disease in thalassemia

51. 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.

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

53. Renal impairment in β-thalassaemia intermedia
50 β-TI patients
median age 28 years
eGFR
median ml/min/1.73 m2
glomerular hyperfiltration in 24 (48%)
negative correlation between eGFR and age
UPr/UCr ratio
median 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 20 40 60 80
100
120
140
160
180
200
300 10 30 50 70
eGFR (mL/min/1.73 m2)
R2: 0.413; p < 0.001
Beta: −1.60 (95% CI: −2.15 to −1.05)
Constant: (95% CI: to )
Age (years)
eGFR = estimated glomerular filtration rate; NTBI = non-transferrin-bound iron; UPr/UCr = urinary protein to creatinine.
Ziaydef F Mussalam KM, et al Kid Int in lress .

54. Tubular Abnormalities
Study on 94 patients with TM:
Sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE).
a significant difference was found in urine NAG activity, a marker of tubular dysfunction, between patients with normal patterns on urine SDS-PAGE and those with tubular or mixed patterns, while the two latter groups did not differ from one another
urine IgG concentration, a marker of glomerular damage, was significantly higher in patients with a mixed pattern on urine SDS-PAGE than in patients with normal patterns or tubular patterns. No significant difference was found between patients with normal patterns on urine SDS-PAGE and patients with tubular patterns.
urine albumin concentration was significantly higher only in patients with mixed patterns on urine SDS-PAGE (between normal and mixed patterns, between mixed and tubular patterns and between normal and tubular patterns). Differences in urine b2-microglobulin concentration could not be established between the three groups.
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.

55. Tubular Abnormalities
Study by Sumboonnanonda et al. on 104 TM patients:
Aminoaciduria in one-third 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 β2 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.

56. Tubular Abnormalities
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.
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.

57. 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.

58. 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.

59. 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:

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

61. The microvasculature of the nephron.
The microvasculature of the nephron. The peritubular capillary plexus is fed by glomerular efferent arterioles and supplies nutrients and oxygen to tubular and interstitial cells. Illustration by Josh Gramling—Gramling Medical Illustrations.
Nangaku M JASN 2006;17:17-25
©2006 by American Society of Nephrology

62. Multiple mechanisms of chronic hypoxia in the kidney.
Multiple mechanisms of chronic hypoxia in the kidney. Mechanisms of hypoxia in the kidney of chronic kidney disease include loss of peritubular capillaries (A), decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells as a result of fibrosis of the kidney (B), stagnation of peritubular capillary blood flow induced by sclerosis of “parent” glomeruli (C), decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances (D), inappropriate energy usage as a result of uncoupling of mitochondrial respiration induced by oxidative stress (E), increased metabolic demands of tubular cells (F), and decreased oxygen delivery as a result of anemia (G).
Nangaku M JASN 2006;17:17-25
©2006 by American Society of Nephrology

63. GFR Abnormalities Study by Ali et al. (Iran) TM (50 patients)
TI (50 patients)
Mean Hb (g/dL)
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
All differences statistically significant
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.

64. 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):

65. 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 (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006; 107:3455–62.

66. 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):

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

68. Questions

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

70. 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

71. Hyperfiltration
Prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) stimulate vasodilation and vasoconstriction, respectively, of renal blood vessels
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.

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

73. Age and the prevalence of albuminuria in adults with sickle cell hemoglobinopathies. □, normoalbuminuria; □, microalbuminuria; ▪, macroalbuminuria.
The development of albuminuria is related in part to age (and therefore, duration of disease). In SS disease, the prevalence of abnormal AER increases from 61% of patients aged 18 to 30 yr to as high as 79% of patients older than 40 yr, so only approximately 20% of patients who have SS disease and are older than 40 yr have normoalbuminuria. More significant, the percentage of individuals with macroalbuminuria doubles between the third and the fifth decades of life: The prevalence of macroalbuminuria is 20% in patients between the ages of 18 and 30 yr but increases to 40% of patients who are older than 40 yr. Similar trends but of a lesser magnitude occur in non-SS sickle hemoglobinopathies: Elevated levels of AER occur in 28% of patients aged 18 to 30 yr but increases to 59% of patients who are older than 40 yr. Macroalbuminuria occurs in 14% of patients with non-SS sickling disorders after the age of 40 yr.
Guasch A et al. JASN 2006;17:
©2006 by American Society of Nephrology

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

75. Figure 1. Intrarenal arterial anatomy.
Figure 1.  Intrarenal arterial anatomy. The main renal artery is divided into four or more segmental arteries that are further subdivided into lobar and interlobar arteries. At the base of each renal pyramid, the interlobar arteries branch into arcuate arteries, which parallel the renal contour along the corticomedullary junction. The arcuate arteries give rise to multiple radial arterial branches called interlobular arteries, which in turn have multiple side branches from the afferent arterioles to the glomeruli. Blood leaves the glomerular capillary network via efferent arterioles, which either form a secondary capillary network around the urinary tubules in the cortex or descend into the renal medulla as long, straight vascular loops called vasa recta. The vasa recta form wide and plentiful vascular bundles at the base of the medullary pyramid, but the bundles taper as they continue distally toward the apex and papilla; as a result, the papillary tip receives only a marginal blood supply, a predisposing factor for ischemia and the subsequent development of renal papillary necrosis.
Jung D C et al. Radiographics 2006;26:
©2006 by Radiological Society of North America

76. 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

77. 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

78. 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.
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. The mean plasma ET-1 levels for SCD patients (dark bars) were significantly higher than those of the controls (blank bars) (*P<0.05). Analysis of variance indicated that SCD status was associated with significantly higher plasma ET-1 levels over the two periods compared with matched controls (P<0.01).
Tharaux P et al. Nephrol. Dial. Transplant. 2005;20:
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please

79. 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).
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:
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please

80. 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

81. Pathophysiology of sickle cell nephropathy
Pathophysiology of sickle cell nephropathy. NSAIDs non-steroidal anti-inflammatory drugs, HF heart failure, RVT renal vein thrombosis, HRS hepato-renal syndrome, NO nitric oxide
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:

82. Mechanisms of renal disease in patients with β-thalassemia.
Musallam K M , Taher A T JASN 2012;23:
©2012 by American Society of Nephrology

83. Current Model of SCN
The current model of sickle cell nephropathy. The environment of the renal medulla is hypertonic, hypoxic, and acidic, causing reversible sickling of red blood cells (RBC). The RBC sickling results in vessel occlusion, ischemia, and microinfarction of the vasa recta. This destruction is believed to trigger the release of vasodilating substances (such as prostaglandins and nitric oxide) that feed back to the glomerulus causing hyperfiltration. With time, hyperfiltration injury leads to glomerulosclerosis, proteinuria, and eventual renal failure
Becker AM. Sickle cell nephropathy: Challenging the conventional wisdom. Pediatr Nephrol. 2011; 26:2099–2109.