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ORIGINAL ARTICLE
Year : 2016  |  Volume : 19  |  Issue : 4  |  Page : 471-474

Prevalence and associations of symptomatic renal papillary necrosis in sickle cell anemia patients in South-Eastern Nigeria


1 Department of Haematology and Immunology, University of Nigeria, Enugu Campus, Enugu, Nigeria
2 Department of Haematology and Immunology, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria
3 Department of Orthopaedics, National Orthopaedic Hospital, Enugu, Nigeria

Date of Acceptance12-Nov-2015
Date of Web Publication1-Jun-2016

Correspondence Address:
Dr. A J Madu
Department of Haematology and Immunology, University of Nigeria, Enugu Campus, PMB 01129, Post Code 400 001, Enugu
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1119-3077.183299

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   Abstract 

Aim: To assess the prevalence and associations of symptomatic renal papillary necrosis (RPN) in sickle cell anemia patients.
Patients and Methods: The case notes of homozygous hemoglobin (Hb) S patients diagnosed with RPN were retrospectively assessed. Diagnosis was based on microscopic hematuria and positive ultrasound findings. Their steady state diastolic blood pressure, Hb, leukocyte count, platelet count, serum direct bilirubin, and aspartate transaminase, were obtained by automated analyzers. These were evaluated for any relationship with the occurrence of RPN.
Results: Two hundred and twenty patients were assessed aged 6–55 years with a median age of 24 years. The prevalence of symptomatic RPN was found to be 2.3%. RPN was positively associated with the female gender (Chi-square P value 0.001), but not with any other clinical or laboratory variable. However, other predictors of disease severity were positively associated with RPN such as age, diastolic blood pressure 0.180 (P = 0.016), serum aspartate transaminase, serum bilirubin 0.145 (0.027), Hb, and leukocyte count − 0.155 (P = 0.003).
Conclusion: The prevalence of symptomatic RPN is low in this group of homozygous S patients and occurs more commonly in females. Improvement in care for these patients will reduce these chronic complications.

Keywords: Female gender, microscopic hematuria, renal papillary necrosis, sickle cell anemia


How to cite this article:
Madu A J, Okoye A E, Ajuba I C, Madu K A, Anigbo C, Agu K. Prevalence and associations of symptomatic renal papillary necrosis in sickle cell anemia patients in South-Eastern Nigeria. Niger J Clin Pract 2016;19:471-4

How to cite this URL:
Madu A J, Okoye A E, Ajuba I C, Madu K A, Anigbo C, Agu K. Prevalence and associations of symptomatic renal papillary necrosis in sickle cell anemia patients in South-Eastern Nigeria. Niger J Clin Pract [serial online] 2016 [cited 2019 Jan 16];19:471-4. Available from: http://www.njcponline.com/text.asp?2016/19/4/471/183299


   Introduction Top


Improving health care and availability of facilities for faster diagnosis and intervention have ensured that sickle cell patients live longer. This has also led to the development of an increasing number of the chronic complications of the disease. The incidence of renal complications in sickle cell has been estimated to be 68% out of which 30–40%[1] have renal papillary necrosis (RPN).

RPN was first observed by Johann Wagner in Ludwig von Beethoven's autopsy report written in 1827 and translated into German by von Seyfreid in 1832.[2] This was hypothesized to be due to chronic alcohol and analgesic abuse. However, until recently the most widely accepted first account was documented by Friedrich in 1877,[3] in a patient with urinary obstruction secondary to prostatic enlargement. Gunther and Edmonson later made the association between RPN and diabetes mellitus,[4],[5],[6] whereas Spuhler was the first to describe analgesic nephropathy. The first observation of RPN in sickle cell was made by Sydenstricker et al., in 1923.[6],[7]

Other causes of RPN aside from sickle cell disease include; pyelonephritis, obstructive uropathy, tuberculosis, hepatic cirrhosis, analgesic abuse, renal transplant rejection/irradiation, diabetes mellitus, and systemic vasculitis.[7] Most of these conditions are associated with ischemia or hypoperfusion of the renal medulla with subsequent necrosis. Two forms of RPN have been widely observed; the medullary form and papillary form, based on the degree of renal parenchymal destruction. In the medullary form, there are discrete grain-sized necrotic areas, with intact fornices, while in the papillary form the entire calyceal systems and papillary surfaces are destroyed and easily outlined.[8] In most patients with RPN, the cause is multi-factorial and more than one of these factors are present. The systemic nature of the causative factors explains the bilateral renal involvement observed in most cases.

There is a wide variability in the clinical features of RPN, which ranges from an asymptomatic microscopic hematuria to acute gross hematuria with fever and flank pain which may lead to acute renal failure. RPN, being vaso-occlusive in etiology has also been known to occur, though with a lesser frequency in heterozygous sickle cell disease patients.[9] It may also be associated with episodes of severe urinary tract infection or prolonged use of analgesics, especially the non-steroidal anti-inflammatory drugs (NSAIDs), used in treating bone pain crisis.[10] Symptomatic and asymptomatic RPN has been recorded to occur with similar frequency in sickle cell disease, 65% and 62%, respectively.[10] Other studies have also estimated the incidence to be 30–40%,[11] though the most detailed study done in 334 patients showed a 39% incidence.[9] Apart from a few severe cases, RPN in sickle cell anemia (SCA) patients infrequently leads to a fatality, in most patients hematuria ceases after bed rest and rehydration with or without blood transfusion.

Investigations for RPN will include; urography, renal ultrasonography, and computerized tomography (CT) or magnetic resonance imaging (MRI) scan of the kidneys. The pathogenetic mechanism is similar to that of other complications in sickle cell disease and involves vaso-occlusion of the vasa recta leading to ischemic necrosis of the renal pyramids (papillae). NSAID's also inhibit cyclooxygenases-1 and 2, which are involved in the synthesis of prostaglandins which have vasodilatory and renoprotective effects.[12] Renal hypoperfusion with tubular and glomerular ischemia ensues, further worsened by red cell sickling and vessel occlusion. The necrosed part subsequently sloughs off with attendant hemorrhage. Imaging techniques therefore show filling defects of loss of echogenicity in the case of renal sonography. More sensitive techniques include helical CT scan, which is expensive and may not be easily afforded by most patients.

The frequency of some chronic complications of sickle cell has been reported to vary widely between different patient populations. In resource-poor settings, in-depth investigation to diagnose RPN may be hampered by affordability of the cost of these investigatory modalities. This research is aimed at ascertaining the frequency of symptomatic RPN in a Nigerian subset of homozygous hemoglobin (Hb) S patients. It will also attempt to define the clinical and laboratory parameters that are associated with the occurrence of RPN.


   Patients and Methods Top


This is a retrospective study of 220 homozygous S patients, seen in the adult sickle cell clinic over a 9 years period (from June 2005 to April 2014). Patients' steady state data were obtained from the case notes, and those who had been diagnosed with papillary necrosis were noted. The diagnosis of symptomatic papillary necrosis was regarded for those patients who had microscopic hematuria and positive ultrasound findings with the exclusion of other causes of hematuria. None of the patients had CT or MRI scan. Ethical approval was obtained from the University of Nigeria Health Research and Ethics Committee.

Data on age, sex, frequency of vaso-occlusive crisis per annum, diastolic blood pressure and steady-state platelet count, white cell count, Hb concentration, serum aspartate transaminase, and direct bilirubin were collected and analyzed. The relationship of these parameters with the occurrence of papillary necrosis was also determined and expressed in figures and tables.

Statistics

This was done using Statistical Package for Social Sciences (SPSS) 17.0, (Illinois, Chicago), USA. The Chi-square test was done to evaluate the relationship for ordinal and nominal variables, while the Kendall's tau-b correlation coefficient (two-tailed) was done for all numerical variables, without assuming equal variance. The P values were assumed to be significant for all values <0.05.


   Results Top


The case notes of 220 homozygous S patients were reviewed; this included 63.5% (139) males and 36.5% (80) females. Their ages ranged from 6 to 55 years with a median age of 24 years, and a mean age of 24.1 ± 7.3 years. The prevalence of symptomatic RPN in SCA was determined to be 2.3% (5). Of the 5 patients who had symptomatic RPN, there were 4 females and 1 male, and there was a significant association between the female gender and occurrence of RPN (Chi-square P value of 0.001).

The mean and median age, Hb concentration, diastolic blood pressure, white cell count, the frequency of crisis per annum, platelet count, aspartate transaminase, and serum direct bilirubin values found in those with and without symptomatic RPN are shown in [Table 1]. [Table 1] also contains the P value as well as the correlation coefficient-Kendall tau-b for all numerical variables. There was no association between the occurrence of RPN and the age, frequency of crisis per annum and the diastolic blood pressure in this group of patients [Table 1]. One hundred and seventeen of the patients in this study had a history of blood transfusion in the past, and this was not significantly associated with the occurrence of papillary necrosis (P = 0.99). The frequency of vaso-occlusive crisis also showed no relationship with the occurrence of symptomatic RPN, Kendall tau-b −0.061 (P = 0.438).
Table 1: Clinical and laboratory parameter in sickle cell patients with and without renal papillary necrosis

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However, significant relationships were found to exist between the age of the patients and the leukocyte count −0.159 (P = 0.001) and platelet count −0.115 (P = 0.025), respectively. In addition, significant association was also noted between the female sex and Hb concentration 0.124 (P = 0.048). Furthermore, a significant inverse relationship was observed between the Hb concentration and the leukocyte count − 0.155 (P = 0.003). The diastolic blood pressure was also observed to be positively associated with patients age 0.180 (P = 0.016). The serum aspartate transaminase was also found to positively correlate with the serum direct bilirubin 0.145 (P = 0.027).

Exploratory plots of these variables were done and are shown in [Figure 1]a and [Figure 1]b. [Figure 1]a is a line plot of the distribution of the patients' age and leukocyte count in patients with and without RPN. The plot indicates that no observable difference exists in for these variables in the patient groups. [Figure 1]b, on the other hand, shows the dot blot of the distribution of the Hb concentration and platelet count in the two groups. This shows some apparent relationship between higher Hb levels and platelet counts in patients with RPN.
Figure 1: (a) Age and leukocyte count of sickle cell anemia patients with and without renal papillary necrosis. 1=Papillary necrosis present; 2=Papillary necrosis absent. (b) Hemoglobin concentration and platelet count in sickle cell patients with and without renal papillary necrosis. 1=Papillary necrosis present; 2=Papillary necrosis absent

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   Discussion Top


There was a low prevalence of symptomatic RPN among our population of SCA patients. This agrees with previous studies involving 74 SCA patients aged 10–52 years in Zaria, North-West Nigeria.[13] RPN is generally painless and therefore unless clinically obvious hematuria is observed, patients may not complain. Furthermore, availability and affordability of diagnostic modalities which include CT, MRI, and urography may also be responsible for this observed apparent low prevalence. In most centers, routine investigation of patients with homozygous Hb S does not include these investigatory modalities. This complication, therefore, is most likely under-diagnosed, and this may explain the low prevalence of symptomatic RPN. However, the occurrence of a lower prevalence of some of the chronic complications of SCA, like sickle leg ulcer [14] and priapism [15] has been recorded in some studies done in Nigerian patients by Madu et al., and this may be a continuation of this observed trend. Also worthy of note is that low prevalence of RPN in homozygous S patients was also recorded in two separate studies by Akinkugbe [16] and Ibinaiye et al.,[13] in South-West and North-Eastern parts of Nigeria, respectively.

Diagnosis of RPN in this study was based on microscopic hematuria with suggestive ultrasonography findings; none of the patients in this study were screened using more sensitive imaging techniques – CT, MRI or urography. This may be further proof that radiological changes indicative of RPN may be seen in most SCA patients even without the occurrence of observable urinary symptoms, as had been hypothesized by Pandya et al.[10]

The patients involved in this study included both adults and children aged 6–55 years with homozygous S, and this may also explain the lower frequencies of RPN observed. The prevalence of symptomatic RPN was found to be 2.3%, this is much less than previous studies done by Odita et al.,[1] who diagnosed their patients using urography and also examined an older patient population (13–51 years). The onset of chronic complications of SCA has been generally observed to be more frequent with increasing age. Analgesic abuse also plays an important etiologic role and is usually seen in patients old enough to self-medicate. The presence of the sickle hemoglobinopathy in those patients with history of prolonged use of NSAIDs further increases the propensity to develop RPN.

The occurrence of symptomatic RPN in homozygous Hb S patients was determined to be significantly associated with the female gender. This has also been observed in diabetics with RPN in the study done by Mandel.[17] However, other clinical and laboratory features of severe sickle cell disease did not show any association with the occurrence of RPN. This may be a further indication that the occurrence of chronic complications in homozygous Hb S patients may be influenced to a large extent by the presence of other environmental and genetic factors. The pathogenesis of RPN is generally thought to be similar to the process involving vaso-occlusion and ischemic necrosis known to occur in SCA. This is further worsens by the low renal medullary oxygen tension. This may require further investigation as this assumption will infer that patients with frequent crisis and severe forms of the disease would most likely have RPN. This observation is contrary to our findings.


   Conclusion Top


RPN can lead to obstructive uropathy renal failure, further adding to the causes of chronic kidney disease in SCA patients. The prevalence of RPN in homozygous S patients has been determined to be 2.3%, and this is lower than the prevalence noted in other geographical locations where SCA is rife. This complication is positively associated with the female gender, but not with other indicators of disease severity. Recent findings support the lower prevalence of complications in some sickle cell patient populations, and this may be due to environmental effects or better patient care.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Odita JC, Ugbodaga CI, Okafor LA, Ojogwu LI, Ogisi OA. Urographic changes in homozygous sickle cell disease. Diagn Imaging 1983;52:259-63.  Back to cited text no. 1
    
2.
Davies PJ. Beethoven's deafness: A new theory. Med J Aust. 1988;149(11-12):644–9.  Back to cited text no. 2
    
3.
Friedrich N. Ueber necrose der nierenpapillen bei hydronephrose. Virchows Arch A Pathol Anat 1877;69:308-12.  Back to cited text no. 3
    
4.
Gunther GW. Die papillennekrosen der niere bei diabetes. Munchen Med Wochenschr 1937;84:1695-99.  Back to cited text no. 4
    
5.
Spühler O, Zollinger HU. Die chronisch-interstitielle Nephritis. Z Klin Med (in German) 1953;151(1):1-50.  Back to cited text no. 5
    
6.
Edmondson HA, Martin HE, Evans N. Necrosis of renal papillae and acute pyelonephritis in diabetes mellitus. Arch Intern Med 1947;79:148.  Back to cited text no. 6
    
7.
Sydenstricker V, Mulherin WH, Houseal RW. Sickle cell anemia: Report of two cases in children, with necropsy in one case. Am J Dis Child 1923;26:132-54.  Back to cited text no. 7
    
8.
Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int 2000;57:1-8.  Back to cited text no. 8
    
9.
Abel MS, Brown CR. Sickle cell disease with severe hematuria simulating renal neoplasm. J Am Med Assoc 1948;136:624.  Back to cited text no. 9
    
10.
Pandya KK, Koshy M, Brown N, Presman D. Renal papillary necrosis in sickle cell hemoglobinopathies. J Urol 1976;115:497-501.  Back to cited text no. 10
    
11.
Alhwiesh A. An update on sickle cell nephropathy. Saudi J Kidney Dis Transpl 2014;25:249-65.  Back to cited text no. 11
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12.
Breyer MD, Hao C, Qi Z. Cyclooxygenase-2 selective inhibitors and the kidney. Curr Opin Crit Care 2001;7:393-400.  Back to cited text no. 12
    
13.
Ibinaiye PO, Babadoko AA, Yusuf R, Hassan A. Renal complications of sickle cell anemia in Zaria, Nigeria: An ultrasonographic assessment. West Afr J Radiol 2013;20:19-22.  Back to cited text no. 13
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14.
Madu AJ, Ubesie A, Madu KA, Okwor B, Anigbo C. Evaluation of clinical and laboratory correlates of sickle leg ulcers. Wound Repair Regen 2013;21:808-12.  Back to cited text no. 14
    
15.
Madu AJ, Ubesie A, Ocheni S, Chinawa J, Madu KA, Ibegbulam OG, et al. Priapism in homozygous sickle cell patients: Important clinical and laboratory associations. Med Princ Pract 2014;23:259-63.  Back to cited text no. 15
    
16.
Akinkugbe OO. Renal papillary necrosis in sickle-cell haemoglobinopathy. Br Med J 1967;3:283-4.  Back to cited text no. 16
    
17.
Mandel EE. Renal medullary necrosis. Am J Med 1952;13:322-7.  Back to cited text no. 17
    


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