medRxiv preprint doi: https://doi.org/10.1101/2024.06.24.24309383; this version posted June 24, 2024.

The copyright holder for this preprint

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

1 High burden of chronic kidney disease of unknown cause among patients receiving renal
2 replacement therapy in Northeast Nigeria: A cross-sectional survey of haemodialysis units.
3
4 Baba Waru Goni1,3,9*, Hamidu Suleiman Kwairanga2,3,4, Aliyu Abdu5, Ibrahim Ummate9, Alhaji
5 Abdu6, Ahmed Ibrahim Ba'aba12, Mohammad Maina Sulaiman9, Loskurima Umar9, Gana M.L10,
6 Aliyu Abdulkadir 7, Sabiu Musa8, Shatuwa Adamu8, Idris A. Usman7, Hauwa Alhaji Sabo7, Idris
7 Musa Abubakar11, Hamza Bukar Adam13, Ismail Alhaji Umar 13, Ayabaryu Papka14, Modu
8 Mustapha14, Yauba Mohammed Saad15, Amin Oomatia16, Mahmoud Bukar Maina3,4 *, Neil
9 Pearce17, Ben Caplin16
10
11 Correspondence to: [email protected] , [email protected]
12
1
13 Department of Medicine, Yobe State University Teaching Hospital Damaturu, Nigeria.
2
14 Department of Human Anatomy, Faculty of Basic and Allied Medical Sciences, College of
15 Medical Science, Gombe State University, Gombe State, Nigeria.
3
16 Biomedical Science Research and Training Centre Damaturu, Yobe State, Nigeria
4
17 TReND in Africa
5
18 Department of Medicine Bayero University Kano/Aminu Kano Teaching Hospital, Kano Nigeria.
6
19 Department of Internal Medicine Federal University Dutse, Jigawa State, Nigeria
7
20 Renal Dialysis Center, Yobe State University Teaching Hospital Damaturu, Nigeria.
8
21 Renal Dialysis Center, Federal Medical Centre Nguru, Yobe State, Nigeria.
9
22 Department of Medicine University of Maiduguri /University of Maiduguri Teaching Hospital,
23 Maiduguri, Borno State, Nigeria.
10
24 Department of Community Medicine, College of Medical Sciences, Yobe State University
25 Damaturu, Nigeria.
11
26 Fatima Abubakar Renal Dialysis Center, State Specialist Hospital Hadejia, Jigawa State, Nigeria.
12
27 African Field Epidemiology Network (AFENET), Yobe State Field Office, Nigeria.
13
28 Abubakar Aliyu Renal Dialysis Center, State Specialist Hospital Maiduguri, Borno State, Nigeria
14
29 Renal Dialysis Center, University of Maiduguri Teaching Hospital, Maiduguri, Borno State,
30 Nigeria.
15
31 Department of Paediatrics University of Maiduguri/University of Maiduguri Teaching Hospital,
32 Borno State, Nigeria
16
33 Centre for Kidney and Bladder Health, University College London, London, UK
17
34 Department of Medical Statistics, London School of Hygiene and Tropical Medicine London,
35 UK.
36
37 ABSTRACT
38
39 Introduction
40 Chronic kidney disease (CKD) is emerging as a significant public health concern in northeastern
41 Nigeria, particularly in states such as Yobe and Borno. Despite its increasing impact, there is a
42 lack of data characterizing this public health issue. This study aims to explore the prevalence,
43 spatial distribution, and risk factors for CKD among patients receiving haemodialysis (HD) in the
44 region.

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
 medRxiv preprint doi: https://doi.org/10.1101/2024.06.24.24309383; this version posted June 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

45
46 Methodology
47 A cross-sectional survey of HD centres in Yobe, Borno, and Jigawa States of Nigeria was
48 conducted. Questionnaire responses were obtained on demographic, social, and clinical data.
49 Spatial analyses were conducted to determine the geographic distribution of the cases.
50
51 Results
52 We identified 376 patients receiving HD services across 4 centres. Of these, 207 (55.1%) were
53 male and the mean age was 46.56 ± 16.4. Most patients reside in urban areas (67.6%). The main
54 pre-dialysis occupations included civil service (100 [26.6%]), agriculture (65 [17.3%]), and trading
55 (58 [15.4%]). 'Hypertension' (195 [51.9%]) was the most common self-reported primary renal
56 disease, followed by unknown causes (70 [18.6%]) and Diabetic Kidney Disease (30 [8%]).
57 Regional analysis demonstrated a particularly high burden of disease in Bade and Jakusko Local
58 Government Areas.
59
60 Discussion and Conclusion
61 Spatial analysis suggests the existence of a CKD hotspot geographically associated with
62 communities along the River Yobe, raising the possibility of an important environmental cause of
63 disease. This study also highlights the lack of access to adequate diagnosis and geographical
64 clustering of CKD burden in this region. These findings further reinforce the need for population-
65 representative studies to characterize the burden of CKD alongside strategic healthcare
66 interventions and collaboration among stakeholders aimed at improving access to care.
67
68 INTRODUCTION
69 CKD is a significant global health issue with an estimated prevalence of 13.4%. 1,2 Its emergence
70 as a major contributor to morbidity and mortality worldwide highlights the significance for
71 comprehensive research and intervention across populations. 1,3 The global rise in CKD is
72 attributed to factors such as diabetes mellitus, hypertension, obesity, and an aging population4.
73 However, regional variations exist, with unique determinants like infections and exposure to
74 environmental toxins contributing to CKD's prevalence in specific areas5.
75
76 CKD of unknown cause (CKDu) has been reported in rural communities of developing countries,
77 including Sri Lanka, India, Central American nations, and North Africa 1. Unlike typical CKD, CKDu
78 is not linked to common risk factors such as hypertension or diabetes. In Nigeria, particularly in
79 the North Eastern region along the Kumadugu River valley, anecdotal reports and small-scale
80 studies have indicated a high prevalence of CKD. 1,3 The Bade community in Northern Yobe State
81 has been identified as a CKD hotspot, with a significant number of CKD cases without a clear
82 underlying cause.6
83
84 To bridge this knowledge gap, we conducted a cross-sectional survey of HD centers in the region.
85 This approach aligns with the 'passive detection' strategies recommended by the International
86 Society of Nephrology’s International Consortium of Collaborators on CKDu.7 The survey aims to
87 delineate the geographic distribution, underlying diagnoses, and risk factors for disease among
88 the HD population in Yobe and surrounding states.
 medRxiv preprint doi: https://doi.org/10.1101/2024.06.24.24309383; this version posted June 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

89
90 METHODS
91
92 Data Collection:
93 Ethical approval for the study was obtained from the study centres, as well as the Yobe State
94 Ministry of Health in Nigeria. Data collection for this study was carried out from January to June
95 2023, coinciding with patients' scheduled HD sessions at designated centers to ensure minimal
96 disruption to their routine care. The study encompassed all HD facilities in the north-eastern
97 states of Borno and Yobe, specifically Yobe State University Teaching Hospital (YSUTH) in
98 Damaturu, Federal Medical Center in Nguru (FMC_Nguru), University of Maiduguri Teaching
99 Hospital (UMTH), and State Specialist Hospital in Maiduguri (SSH_Maiduguri). Additionally, State
100 Specialist Hospital Hadejia (SSH_Hadejia) in Jigawa State was included to provide a broader
101 perspective on the CKD prevalence in the region. Despite Jigawa's location in northwestern
102 Nigeria, Hadejia is the largest town in the north-eastern part of Jigawa state potentially providing
103 treatment for patients living in Yobe state.
104
105 Patients were individually approached for participation, and informed consent was secured from
106 each before inclusion in the study. Trained data collectors then administered a comprehensive,
107 researcher-adapted questionnaire to those who consented. This questionnaire was designed to
108 capture a range of information, including demographic details (age, gender), clinical data
109 (duration and frequency of dialysis treatments), and potential factors contributing to the etiology
110 of CKD. Additional relevant variables, such as occupation and residential history, were also
111 gathered to support a multifaceted analysis of CKD within the population.
112
113 Table 1 Inclusion And Exclusion Criteria
114
Inclusion Criteria
1. Individuals receiving HD treatment at the selected HD centers between January 2023
and June 2023
2 Patients who were diagnosed with established CKD.
3 Patients who provided informed consent to participate in the study.
Exclusion Criteria
1 Patients undergoing HD treatment outside the designated study centers even if they
were living in the state under study.

2 Individuals with acute kidney injury (AKI), which is defined as an abrupt decrease in
kidney function that includes both injury (structural damage) and impairment (loss
of function).
3 CKD patients who are not on HD
4 Those who did not provide informed consent.
5 CKD patients receiving HD services at more than one centre.
115
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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116 Data Analysis:

117 Data analysis was performed using Python 3.10. Descriptive statistics in the form of mean (SD),
118 median (IQR) and frequencies were used to characterize the study population. Geographical data
119 was presented using geopandas and geoplots for mapping HD prevalence across the study region.
120 Data visualizations, including bar charts and heatmaps, were created using matplotlib and
121 seaborn.
122
123 RESULTS
124
125
126 Description of study population by centre
127
128 The study enrolled 376 participants (Table 2), with a higher proportion of males (55.1%) than
129 females (44.9%). Variations in sex distribution were observed among centers, with YSUTH having
130 the highest male representation (61.6%) and FMC_Nguru reporting the highest female
131 representation (54.5%). The mean age was 46.56 ± 16.4 years, varying across centers. SSH
132 Maiduguri and UMTH had the highest urban representation (91.9% and 75.6% respectively). Civil
133 servants comprised 26.6% of participants, with SSH_Maiduguri reporting the highest proportion
134 (38.4%). Traders accounted for 15.4%, again with SSH_Maiduguri reporting the highest (27.3%).
135 The agriculture sector represented 17.3%. Transport and fishing occupations were less
136 represented, and no participants were from the mining sector.
Table 2: Description of study population by centre
Variables All centres ysuth umth ssh_maiduguri fmc_nguru ssh_hadeja
Number of patients
376(100) 112(29.8) 86(22.9) 99(26.3) 44(11.7) 35(9.3)
[Count(%)]
Age (Mean±SD) 46.56±16.4 44.79±16.4 45.73±17.6 45.73±13.8 55.93±15.4 44.89±17
Male 207(55.1) 69(61.6) 47(54.7) 50(50.5) 20(45.5) 21(60)
Sex
Female 169(44.9) 43(38.4) 39(45.3) 49(49.5) 24(54.5) 14(40)
Mean Duration receiving
10.1±9.5 8.49±6.1 16.22±12.9 7.78±5.9 5.68 ± 2.5 12.29 ± 13.4
HD (in months)
Urban/rural (pre-dialysis Urban 254(67.6) 60(53.6) 65(75.6) 91(91.9) 24(54.5) 14(40)
residence) Rural 122(32.4) 52(46.4) 21(24.4) 8(8.1) 20(45.5) 21(60)
Main occupation pre–
Agriculture 65(17.3) 27(24.1) 5(5.8) 14(14.1) 12(27.3) 7(20)
dialysis
Fishing 6(1.6) 3(2.7) 2(2.3) 1(1) 0(0) 0(0)
Civil Servants 100(26.6) 22(19.6) 31(36) 38(38.4) 4(9.1) 5(14.3)
Mining 0(0) 0(0) 0(0) 0(0) 0(0) 0(0)
Traders 58(15.4) 12(10.7) 13(15.1) 27(27.3) 1(2.3) 5(14.3)
Transport 7(1.9) 2(1.8) 2(2.3) 1(1) 2(4.5) 0(0)
Others 140(37.2) 46(41.1) 33(38.4) 18(18.2) 25(56.8) 18(51.4)
137
 Table 3: Self-reported primary renal disease
Variables All centres ysuth umth ssh_maiduguri fmc_nguru ssh_hadeja
GN 43(5.9) 4(3.6) 14(16.3) 9(9.1) 11(25) 5(14.3)
Self-reported DKD 30(8) 6(5.4) 8(9.3) 6(6.1) 4(9.1) 6(17.1)
primary renal ‘Hypertension’ 195(51.9) 60(53.6) 24(27.9) 72(72.7) 24(54.5) 15(42.9)
disease Unknown 70(18.6) 36(32.1) 18(20.9) 12(12.1) 1(2.3) 3(8.6)
Other 22(5.9) 4(3.6) 13(15.1) 0(0) 1(2.3) 4(11.4)
Yes 25(6.6) 1(0.9) 4(4.7) 2(2) 16(36.4) 2(5.7)
Had renal biopsy
No 351(93.4) 111(99.1) 82(95.3) 97(98) 28(63.6) 33(94.3)
Yes 35(9.3) 6(5.4) 11(12.8) 5(5.1) 5(11.4) 8(22.9)
Diabetes
No 341(90.7) 106(94.6) 75(87.2) 94(94.9) 39(88.6) 27(77.1)
Yes 238(63.3) 75(67) 42(48.8) 65(65.7) 32(72.7) 24(68.6)
Hypertension
No 138(36.7) 37(33) 44(51.2) 34(34.3) 12(27.3) 11(31.4)
Yes 8(2.1) 0(0) 5(5.8) 3(3) 0(0) 0(0)
HIV
No 368(97.9) 112(100) 81(94.2) 96(97) 44(100) 35(100)
Yes 6(1.6) 2(1.8) 1(1.2) 0(0) 2(4.5) 1(2.9)
TB
No 370(98.4) 110(98.2) 85(98.8) 99(100) 42(95.5) 34(97.1)
138
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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139 The distribution of self-reported primary renal diseases among patients in the selected centers
140 (Table 3) showed the diverse etiologies contributing to CKD. Hypertension was identified as the
141 most common self-reported primary renal disease, comprising 51.9% of patients across all
142 centers. State Specialist Hospital Maiduguri reported the highest proportion of patients
143 attributing their CKD to hypertension at 72.7%. Unknown etiology accounted for 18.6% overall,
144 with the highest proportion at YSUTH Damaturu at 32.1%. Diabetic Kidney Disease (DKD) and
145 Glomerulonephritis (GN) were other notable self-reported primary renal diseases, representing
146 8% and 5.9% of patients, respectively, across all centers. Among these, FMC Nguru reported the
147 highest proportion of patients with DKD at 9.1% and GN at 25%. Additionally, the category
148 "Other" encompassed 5.9% of patients, with variations among centers.
149
150 Number of CKD Patients receiving HD (CKD-HD) by Local Government Area (LGA)
151
152 The prevalence of CKD-HD varied across local government areas within the study region. In Bade
153 Local Government Area of Yobe State, the prevalence was notably high, with 11 per 100,000
154 individuals on HD (7–15 per 100,000 at a 95% confidence interval) (Table 4). This was closely
155 followed by Jakusko LGA of Yobe State with 8 per 100,000. Nguru, Damaturu, Bursari, Potiskum,
156 Tarmuwa, and Yunusari LGAs all had a prevalence between 3 and 4 per 100,000, while all other
157 areas had a prevalence of less than 2 per 100,000.
158
159 In Borno State, Askira/Uba had the highest prevalence of CKD-HD, with a prevalence of 6 per
160 100,000 individuals on dialysis, followed by Gwoza with 5 cases per 100,000 individuals. Beyond
161 these, no other local government area in Borno State had a prevalence exceeding 3 per 100,000
162 individuals. For the northeastern zone of Jigawa State which constitutes eight local government
163 areas (Auyo, Birniwa, Guri, Hadejia, Kafin Hausa, Kaugama and Kiri Kasama), the number of
164 observed HD patients with CKD was generally low, with all areas reporting less than 2 cases per
165 100,000 individuals, except for Hadejia, which stood out with 5 cases per 100,000 individuals.
166
Table 4: Prevalence of HD for CKD in some selected LGAs in Yobe and Borno States
Confidence
Interval(95%)
Number of Sample
Estimated Lower Upper
LGA State Reported Proportion
Population Limit Limit
Cases (Per 105)
Bade Yobe 35 321,241 11.0 7.3 15.0
Jakusko Yobe 13 163,035 8.0E 4.0 12.3
Askira-Uba Borno 16 273,085 6.0E 3.0 9.0
Gwoza Borno 11 229,998 5.0E 2.0 8.0
167
168 Spatial Distribution of CKD Cases
169
170 Our spatial analysis revealed marked regional disparities in CKD-HD prevalence within the
171 surveyed states (Figure 1). The choropleth maps (Panels A, B, C, and D) indicate a higher
 medRxiv preprint doi: https://doi.org/10.1101/2024.06.24.24309383; this version posted June 24, 2024. The copyright holder for this preprint
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172 concentration of CKD cases in Yobe and Borno states, particularly in the Bade and Askira/Uba
173 Local Government Areas, which reported the highest incidences of 11 and 6 cases per 100,000
174 individuals, respectively

175
176
177
178

179
180
181
182
183 Figure 1: Spatial Distribution of Reported CKD-HD Cases by State and Local Government of Patient
184 Origin. A: Choropleth Map Illustrating the Study Area and Total CKD Cases by States. B, C, & D:
185 Choropleth Maps Depicting the Number of Reported CKD-HD Cases per hundred thousand of the
186 individuals at the Local Level for Three States, with Yellow Points Signifying Settlement
187 Distribution and blue crosses signifying the dialysis centers.
188
189
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190 DISCUSSION
191
192
193 We investigated the number of individuals receiving HD within the northeastern Nigeria.
194 Focusing on some selected HD units in Yobe, Borno, and Jigawa states, our study aimed to provide
195 a comprehensive understanding of CKD in Northeastern Nigeria. We estimated population
196 numbers from the 2006 census data and reported population growth by WHO. 8,9 We collected
197 the number of reported dialysis-dependent CKD cases in the study area and presented the
198 distribution of CKD patients receiving HD across the local government areas of Yobe, Borno. We
199 used HD as surrogate for CKD in the study, because a lot of CKD patients in the community may
200 be asymptomatic and therefore may not come to hospital.
201
202 Notable findings include localized clusters of CKD patients receiving HD in the selected centers
203 from certain local governments, such as Bade and Jakusko in Yobe State, Askira-Uba, and Gwoza
204 in Borno State. We encountered challenges in accurately categorizing the primary renal disease
205 (PRD) due to limitations in diagnostic facilities, especially for renal biopsy. Despite these
206 obstacles, our findings revealed a number of cases of CKD of unknown etiology, emphasizing the
207 urgency of enhanced healthcare infrastructure and targeted research efforts in the region.
208 In our study, we found that many CKD patients on HD reported hypertension as their PRD.
209 However, it’s important to clarify that in most cases, hypertension was identified for the first time
210 after presenting with clinical features of CKD, suggesting that hypertension was secondary to,
211 rather than a primary cause of CKD. In addition, most patients in the study did not have their
212 previous medical records, so we could not assess their premorbid medical history. Given the
213 widespread presence of hypertension in the study area and its connection to kidney disease, it is
214 possible that some of these CKD-HD cases may be unknown or secondary to a known cause such
215 as IgA nephropathy etc since the cases were never biopsied or comprehensively investigated.
216
217 The relatively high number of HD patients in Yobe State compared to the observed rates in
218 previous studies for West Africa, Jigawa and Kano in the northwest and even other north eastern
219 states such as Borno and Bauchi States emphasizes the regional variability and complexity of the
220 CKD landscape in Nigeria and may be potentially attributed to various factors such as
221 environmental, genetic, and possible geoclimatic factors that differ across these regions. 10–12 It
222 is also important to emphasize the challenges observed by Okoye and Mamven’s analysis of HD
223 in Nigeria, where they stated that limited access to dialysis may contribute to underestimations
224 of CKD prevalence.13 The relationships between our localized study and these insights emphasize
225 the urgent need for comprehensive strategies to accurately identify and address CKD in northern
226 Nigeria. Our study exclusively focused on patients receiving HD which may serve as surrogate for
227 CKD; offering a limited perspective and/or a limitation on end-stage kidney disease (ESKD) within
228 this specific cohort. It should therefore be noted that our study did not include pre-dialysis CKD,
229 which will influence the observed prevalence and patterns of CKDu in the broader population.
230 Furthermore, the prevalence of CKD observed among HD patients may not fully reflect the true
231 extent of the CKD burden in the regions, as the majority of residents may face financial and
232 geographic barriers limiting their access to HD services. Given the relatively high costs associated
233 with HD in low-and-middle income countries (LMICs), individuals with CKD who cannot afford or
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234 access this treatment might remain undiagnosed and unaccounted for in our study. Also, factors
235 such as cultural norms, may significantly impact women’s ability to receive dialysis.
236
237 These findings suggest the urgent need for targeted interventions, including improved access to
238 affordable healthcare, community-based CKD screening programs, and enhanced infrastructure
239 for early detection and management of CKD in the region.
240
241 Bade and Jakusko Local Government Areas were identified as potential hotspots, exhibiting a
242 notably high prevalence of CKD cases. One potentially important factor may be their source of
243 drinking water. The predominant source in these communities was borehole water, with a
244 substantial proportion of patients using sachet water, which also originates from boreholes. This
245 highlights the importance of investigating the quality of water, as a potential causative factor for
246 CKD in the region. The elevated number of cases in Hadejia also raises questions about potential
247 contributing factors. The presence of a river connecting Hadejia with northern Yobe State14 may
248 facilitate the transmission of environmental contaminants or pathogens that could influence CKD
249 prevalence. The distribution of dialysis centres and settlement patterns suggests that access to
250 healthcare services and population density may play roles in the observed CKD distribution. This
251 heterogeneity highlights the need for tailored healthcare interventions in the Northeastern
252 region.
253
254 Males constitute the majority of cases in our study, with a particularly strong male presence
255 observed at YSUTH and State SSH_Maiduguri. Conversely, SSH_Hadejia displays a more balanced
256 gender distribution. This variance suggests the influence of distinct regional factors on CKD
257 prevalence and aligns with previously reported region-specific trends of CKD in the north-eastern
258 part of Nigeria.6 The variations may also highlight the possible lack of access to care by women.
259 The reason why majority of CKD patients at the two HD centres in Borno State (i.e. UMTH and
260 SSH Maiduguri) reported being resident in urban area may be due to population displacement as
261 a result of over a decade of ‘Boko Haram’ insurgency in the region. The protracted armed conflict
262 displaced most of the rural population in Borno state. This displaced rural population are now
263 residing among host community and designated Internally Displaced Persons’ (IDP) camps in the
264 capital city of Maiduguri.
265
266 CONCLUSIONS AND RECOMMENDATIONS
267
268 In conclusion, this study sheds light on the proportions of Yobe and Borno State populations
269 receiving HD. The spatial distribution analysis reveals potential geographic clusters of CKD cases,
270 in specific areas, such as Bade and Jakusko Local Government areas of Yobe State. While
271 geographic proximity and shared water resources may play a role in the observed prevalence in
272 some regions, comprehensive epidemiological investigations are essential to understand the
273 nature of CKD's causative factors. In addressing the CKD challenge in northeastern Nigeria,
274 collaboration between healthcare authorities, researchers, and communities is crucial.
275
276 To obtain a more accurate representation of CKD prevalence in the general population,
277 comprehensive community-based surveys are crucial. Such an approach would enable the
 medRxiv preprint doi: https://doi.org/10.1101/2024.06.24.24309383; this version posted June 24, 2024. The copyright holder for this preprint
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278 inclusion of a broader range of socioeconomic groups, providing valuable insights for public
279 health initiatives, resource allocation, and interventions to address the wider CKD landscape in
280 northeastern Nigeria. Environmental factors such as the source of drinking water and potential
281 agricultural contaminants, socioeconomic disparities, limited healthcare infrastructure, climatic
282 conditions like heat stress, and challenges in accessing timely medical services.
283
284
285 Supplementary Materials
286 The raw data, Images, and codes for the analysis are available here
 medRxiv preprint doi: https://doi.org/10.1101/2024.06.24.24309383; this version posted June 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

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