|Year : 2019 | Volume
| Issue : 2 | Page : 72-75
Correlation between nephropathy and ophthalmic complications in cases of sickle cell anemia: An entangled association
Aditi Pareek1, Aditya Khandekar1, Sourya Acharya1, Pravin Tidake2, Samarth Shukla3
1 Department of Internal Medicine, Jawaharlal Nehru Medical College, Wardha, Maharashtra, India
2 Department of Ophthalmology, Jawaharlal Nehru Medical College, Wardha, Maharashtra, India
3 Department of Pathology, Jawaharlal Nehru Medical College, Wardha, Maharashtra, India
|Date of Submission||24-Jan-2019|
|Date of Decision||12-Mar-2019|
|Date of Acceptance||25-Mar-2019|
|Date of Web Publication||24-May-2019|
Dr. Aditya Khandekar
Jawaharlal Nehru Medical College, Sawangi (Meghe), Wardha - 442 001, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Sickle cell disease commonly presents with unpredictable episodes of vasocclusion and pre mature RBC destruction, which manifest as acute pain and tissue ischemia. In kidneys, endothelial dysfunction occurs in the nephron leading to microalbuminuria, vaso-occlusion, ischemia, infarction, and ultimately nephron loss. Proliferative and non-proliferative retinal changes can also occur, due to similar underlying pathophysiology of vasospasm. Aims and Objectives: To study the correlation between Sickle Cell Nephropathy and Ophthalmic Complications in cases of Sickle Cell disease. Materials and Methods: Thirty five adults aged 18 to 60 years, having Sickle Cell disease were selected as study participants. Complete blood analysis was carried out, with assessment of Urine Albumin: Creatinine ratio and ophthalmic findings, studied by direct and indirect ophthalmoscopy, and slit-lamp biomicroscopy. Results: Patients were divided into two categories: Category I comprising of 7 patients who were admitted to the Medicine ICU with Crisis, and Category II comprising of 28 clinically stable patients. 5 patients from Category I (71.4%), and 2 patients from Category II (7.1%), were found to have findings of peripheral retinopathy. Category I patients had received a mean of 6.17 ± 2.14 blood transfusions, Category II patients had received 2.89 ± 1.81 transfusions, difference being statistically significant. Mean Hb in Category I patients was 6.37 ± 0.35 gm/dl, compared to 7.95 ± 0.81 gm/dl in Category II patients. The mean Urine Albumin/ Creatinine ratio of patients having Ophthalmic manifestations was found to be 286.71 ± 74.75 mg/g, while the mean Urine Albumin/ Creatinine ratio of patients with no Ophthalmic manifestations was found to be 31.82 ± 4.48 mg/g, difference being statistically significant. Conclusion: Sickle Cell nephropathy and retinopathy appear to stem as manifestations of a common underlying mechanism of sickle vasculopathy, and thus can be studied as markers for each other.
Keywords: Sickle cell disease, sickle nephropathy, sickle retinopathy, urine albumin/creatinine ratio
|How to cite this article:|
Pareek A, Khandekar A, Acharya S, Tidake P, Shukla S. Correlation between nephropathy and ophthalmic complications in cases of sickle cell anemia: An entangled association. Indian J Med Spec 2019;10:72-5
|How to cite this URL:|
Pareek A, Khandekar A, Acharya S, Tidake P, Shukla S. Correlation between nephropathy and ophthalmic complications in cases of sickle cell anemia: An entangled association. Indian J Med Spec [serial online] 2019 [cited 2019 Jun 26];10:72-5. Available from: http://www.ijms.in/text.asp?2019/10/2/72/258990
| Introduction|| |
Sickle cell disease (SCD) is caused by a mutation in the beta-globin gene that changes the amino acid from glutamic acid to valine forming HbS, provoking unpredictable episodes of vaso-occlusion and premature RBC destruction, which manifests as acute pain and tissue ischemia. Evidence of renal disease begins and often progresses to chronic kidney disease. In Central India, also known as the sickle cell belt, patients develop relatively severe manifestations compared to peers in other parts of India and developed countries, vaso-occlusive crises and strokes being the major manifestations.,,
In the kidneys, endothelial dysfunction occurs in the nephron leading to microalbuminuria, vaso-occlusion, ischemia, infarction, and ultimately nephron loss. Studies have shown that among HbSS/HbSβ(0), abnormal albuminuria is associated with lower baseline hemoglobin. Albuminuria is considered to be a relevant biomarker for the detection of early glomerular damage in patients with SCD. Serum creatinine may be associated with renal insufficiency in sickle cell patients. When serum creatinine is elevated, the disease has reached an advanced stage of renal failure. The early recognition of sickle cell nephropathy (SCN) together with identification of the associated clinical and biological risk factors is, therefore, crucial, to initiate kidney-protective therapy at early stages of renal impairment.,
Ophthalmic complications can be grouped into proliferative and nonproliferative retinal changes based on the presence of vascular proliferation. Visual impairment secondary to proliferative sickle retinopathy (PSR) is more common in patients with hemoglobin (Hb) SC genotype.,,
Thus, this study was undertaken with the aim of assessing the correlation between SCN and ophthalmic complications in cases of SCD.
| Methodology|| |
After obtaining due permission from the Institutional Ethics Committee, a prospective cross-sectional study was conducted in collaboration with the Department of Medicine, Department of Nephrology, Department of Ophthalmology, and Central Clinical Laboratory of Acharya Vinoba Bhave Rural Hospital, a 250-bedded tertiary care center in Sawangi (Meghe), Wardha, for a period of 2 months from June 1, 2018, to July 31, 2018.
The study participants selected were 35 adults aged 18–60 years, clinically diagnosed as having SCD by Haemoglobin quantitative electrophoresis, attending the medicine outpatient department (OPD), sickle cell OPD, or admitted in the medicine ward or intensive care unit (ICU).
Exclusion criteria considered were as follows:
- Patients having additional blood dyscrasias such as thalassemias
- Patients suffering from any chronic infection, collagen vascular disease, or known cases of long-standing diabetes mellitus, or hypertension
- Patients on anti-inflammatory medication, including glucocorticoid or Cox-inhibitor therapy.
Written consent of the participant was then obtained, having explained in detail about the purpose, methodology, and implications of the study. Next, a proforma detailing relevant clinical history was obtained.
Collection and analysis of blood sample
Blood sampling was first done by venipuncture as per the standard procedure, for estimation of Hb, total leukocyte count (TLC), and absolute platelet count (APC) which was done using a ABX Pentra XL 80 CBC Analyzer manufactured by Horiba Ltd.
Calculation of urine albumin and creatinine
Due to the problems associated with incomplete collection of a 24-h urine sample, albumin-to-creatinine ratio (ACR) was measured in a random urine sample. Normal ACR was <30. Values obtained were classified as follows: 30–300 being microalbuminuria and >300 being macroalbuminuria.
Urine ACR (UACR) in mg/g = Urine albumin in mg/dl/urine creatinine in g/dl.
Unlike a dipstick test for albumin, it is unaffected by variation in urine concentration and was thus taken to be an ideal marker. UACR was assessed using a CLINITEK Advantus® Urine Chemistry Analyzer, manufactured by Siemens Healthineers, a division of Siemens Ltd.
Ophthalmic procedures carried out
A detailed dilated eye examination was then performed including direct ophthalmoscopy, indirect ophthalmoscopy, and slit-lamp biomicroscopy. SCD patients having mature senile cataracts, positive anterior/posterior segment pathology, or glaucoma were excluded from ophthalmic examination.
The media and disc characteristics including color, cup, size, shape, margins, blood vessels, peripheral macula, and the foveal reflex were then evaluated.
The data obtained were entered in Microsoft Office Excel version 2010 (Microsoft Corporation, Redmond, Washington, United States), and statistical analysis was carried out using inferential statistics, including Chi-square test and Student's t-test. Software used for the analysis was SPSS version 22.0 (IBM Corporation, Armonk, New York, United States), with P < 0.05 being considered as statistically significant.
| Results|| |
Thirty-five adults, aged 18–60 years, clinically diagnosed as having SCD by Hb quantitative electrophoresis, attending the medicine OPD, sickle cell OPD, or admitted in the medicine ward or ICU were selected as the study participants. Of the 35 patients, 7 (20%) presented to us with sickle cell crisis, whereas 28 (80%) others had come either for periodic follow-up or for minor symptoms. Thus, the 35 patients were divided into two categories, Category I comprising patients who were admitted to the medicine ICU with crisis and Category II comprising clinically stable patients without crisis, who presented to the OPD, or were admitted to the ward.
On evaluation of chief complaints that patients presented with, 18 patients (51.4%) gave a history of chronic fatigue and malaise, whereas 11 patients (31.4%) complained of backaches. Ten patients (28.5%) had experienced recurrent upper respiratory tract infections (URTIs), whereas 5 patients (14.2%) had a history of long-standing bone pain. Of the 7 patients, 2 patients, who presented to the casualty in crisis, had acute-onset chest pain (28.5%), and on fundoscopy later, they were also found to have ophthalmic manifestations of sickle cell retinopathy. A comparison of clinical features among Category I and Category II patients is presented in [Table 1].
|Table 1: Comparison of chief complaints among Category I and Category II patients|
Click here to view
On fundoscopic examination, 5 patients (71.4%) out of 7 Category I patients and 2 patients (7.1%) out of 28 Category II patients were found to have findings of peripheral retinopathy. Parameters compared included common vascular changes in sickle cell anemia and Goldberg's staging of PSR. Results of the fundoscopic examination were found to be statistically significant in Category I patients in comparison to patients from Category II, having t-value 4.01 and P < 0.01, as depicted in [Table 2].
On eliciting a history of blood transfusions, the mean number of transfusions that Category I patients had received was 6.17 ± 2.14, whereas the mean number of transfusions that Category II patients had received was 2.89 ± 1.81. This was statistically significant, having t value 9.37 and P < 0.01. Next, an assessment of laboratory parameters among sickle cell patients was carried out. On estimation of Hb, the mean Hb among the Category I patients was 6.37 ± 0.35 g/dl, whereas Category II patients had a mean Hb of 7.95 ± 0.81 g/dl, a parameter which proved to be statistically significant as well, having t value 4.96 and P < 0.01.
The mean UACR of patients having ophthalmic manifestations was found to be 286.71 ± 74.75 mg/g, whereas the mean UACR of patients with no ophthalmic manifestations was found to be 31.82 ± 4.48 mg/g, having t value 9.19 and P < 0.01.
| Discussion|| |
When ophthalmic findings were evaluated across age and gender, there was no specific correlation obtained favoring patients of a particular age or showing greater prevalence in a particular gender. Correlation of ophthalmological signs to the duration of clinical features also was proved to be nonsignificant, so common clinical features that patients presented to the ward/ICU with were listed next and included malaise, back pain, recurrent URTIs, bone pain, and chest pain.
A positive correlation was obtained among patients having greater morbidity due to sickle cell anemia and more significant clinical features (P = 0.036, significant). The number of blood transfusions was noted to be significant in correlation to severity of clinical features (P< 0.01). Furthermore, the mean Hb was found to be a significant parameter in predicting sickle cell retinopathy (P< 0.01, significant), as lower Hb levels indicated long-standing and/or more severe disease, which plays a key role in alteration of the retinal vascular bed.
Renal damage is known to be a progressive complication that starts during adolescence in sickle cell patients, and if not treated early, it can proceed to cause renal failure, with mortality reaching 12% in adults homozygous for the sickle cell gene. Microalbuminuria, an early manifestation of renal parenchymal damage, can occur in up to 30%–60% of SCD patients, with prevalence increasing with age. Hyperfiltration and microalbuminuria alter the UACR, making it useful as a tool for screening. Other characteristic renal manifestations of SCD include renal ischemia, microinfarcts, papillary necrosis, and alterations of tubular function. Studies have found the severity of sickle nephropathy to reduce with progressive treatment using hydroxyurea. The mean UACR of 286.71 ± 74.75 mg/g among patients who had ophthalmic manifestations that we obtained in our study makes it a factor which should warrant rapid and periodic fundoscopic examination to prevent sickle retinopathy, along with maintenance of hydration, prompt treatment of infections, and proper titration of hydroxyurea therapy to ensure the best outcomes for patients.
Another serious complication of SCD is sickle cell retinopathy, classical findings of which can include arteriolar occlusion, perivenous hemorrhages, vessel tortuosity, and areas of retinal ischemia. Studies have documented up to 54.6% of SC patients and 18.1% of Homozygous sickle cell anaemia (SS) patients developing Grade 3–5 proliferative sickle cell retinopathies. Even though there are no specific clinical signs that can predict the progress of SCD to involve the retinal vascular system, a few authors have found that patients presenting with crisis and splenic sequestration should be considered for early ophthalmic evaluation. Furthermore, patients with G6PD deficiency should be taken for early screening, as it has been documented to be an important predisposing factor in accelerating progression to retinopathy. Still, most patients retain acceptable vision since the retinopathy occurs in the periphery, and any associated “sea-fan” neovascularization has a high tendency for autoinfarction, regressing spontaneously. Thus, vision loss from sickle retinopathy is largely preventable via regular fundoscopic examinations and treatment as indicated. Wide-field fluorescein angiography and color imaging can aid identification of peripheral vascular remodeling and assessment of high-risk characteristics for proliferative retinopathy. Treatment of sickle cell retinopathy today is being carried out using modalities such as photocoagulation and cryotherapy to treat neovascularization.
| Conclusion|| |
Thus, two major complications of SCD, i.e., nephropathy and retinopathy are phenomena that can be effectively controlled if detected early. They both appear to stem as manifestations of a common underlying mechanism of sickle vasculopathy and thus can be considered to be markers for each other, an observation that we would like to confirm by a larger multicentric study. UACR appears to be a good predictor of the natural course of the disease, which progresses to retinopathy, and we would thus like to propose the two phenomena as revised indications for the initiation of hydroxyurea therapy, since the current guidelines for starting treatment do not include markers of sickle nephropathy or ophthalmic manifestations of the disease.
As was outlined by the study, if patients at a greater risk are identified early on, namely those who have a more significant history of previous blood transfusions, lower Hb levels at presentation, long-standing clinical features, or raised UACRs, such patients can be guided to initiate regular fundoscopic examinations and thus prevent development of peripheral retinopathy. This can be a key step in reducing the overall ophthalmic morbidity due to sickle cell anemia and bring down the treatment burden and incidence of complications for rural health centers as well the patients themselves.
Limitations of the study
The study is an ICMR-STS research and was thus completed in the stipulated time period of 2 months, in the author's institution itself. A multi-centric study conducted over a longer time-frame would yield more accurate data regarding the correlation of nephropathy to ophthalmic complications in Sickle Cell disease.
The authors wish to acknowledge ICMR-STS for provision of the research studentship 2018.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jameson J, Kasper D, Fauci A, Hauser S, Longo D, Loscalzo J, et al
. Harrison's Principles of Internal Medicine. 19th
ed. New York, NY: McGraw-Hill Education; 2015. p. 635-6.
Guasch A, Cua M, Mitch WE. Early detection and the course of glomerular injury in patients with sickle cell anemia. Kidney Int 1996;49:786-91.
Jain D, Arjunan A, Sarathi V, Jain H, Bhandarwar A, Vuga M, et al.
Clinical events in a large prospective cohort of children with sickle cell disease in Nagpur, India: Evidence against a milder clinical phenotype in India. Pediatr Blood Cancer 2016;63:1814-21.
Celik T, Unal S, Ekinci O, Ozer C, Ilhan G, Oktay G, et al.
Mean platelet volume can predict cerebrovascular events in patients with sickle cell anemia. Pak J Med Sci 2015;31:203-8.
Jain D, Warthe V, Dayama P, Sarate D, Colah R, Mehta P, et al.
Sickle cell disease in central India: A potentially severe syndrome. Indian J Pediatr 2016;83:1071-6.
Audard V, Bartolucci P, Stehlé T. Sickle cell disease and albuminuria: Recent advances in our understanding of sickle cell nephropathy. Clin Kidney J 2017;10:475-8.
Lichtman M. Williams Manual of Hematology. 9th
ed. New York, NY: McGraw-Hill Education/Medical; 2015. p. 581-605.
Do BK, Rodger DC. Sickle cell disease and the eye. Curr Opin Ophthalmol 2017;28:623-8.
Menaa F, Khan BA, Uzair B, Menaa A. Sickle cell retinopathy: Improving care with a multidisciplinary approach. J Multidiscip Healthc 2017;10:335-46.
Feroze KB, Azevedo AM. Retinopathy, Hemoglobinopathies. Treasure Island (FL): StatPearls Publishing; 2017.
Gustave BW, Oliver SC, Mathias M, Velez-Montoya R, Quiroz-Mercado H, Olson JL, et al.
Reversal of paracentral occlusive retinopathy in a case of sickle cell disease using exchange transfusion. Ophthalmic Surg Lasers Imaging Retina 2013;44:505-7.
Tehseen S, Joiner CH, Lane PA, Yee ME. Changes in urine albumin to creatinine ratio with the initiation of hydroxyurea therapy among children and adolescents with sickle cell disease. Pediatr Blood Cancer 2017;64. doi: 10.1002/pbc.26665.
Alhwiesh A. An update on sickle cell nephropathy. Saudi J Kidney Dis Transpl 2014;25:249-65.
] [Full text]
Leveziel N, Lalloum F, Bastuji-Garin S, Binaghi M, Bachir D, Galacteros F, et al.
Sickle-cell retinopathy: Retrospective study of 730 patients followed in a referral center. J Fr Ophtalmol 2012;35:343-7.
Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: Correlation with clinical factors. J AAPOS 2011;15:49-53.
Scott AW. Ophthalmic manifestations of sickle cell disease. South Med J 2016;109:542-8.
Cho M, Kiss S. Detection and monitoring of sickle cell retinopathy using ultra wide-field color photography and fluorescein angiography. Retina 2011;31:738-47.
Cohen SB, Fletcher ME, Goldberg MF, Jednock NJ. Diagnosis and management of ocular complications of sickle hemoglobinopathies: Part V. Ophthalmic Surg 1986;17:369-74.
[Table 1], [Table 2]