Role of novel biomarkers in predicting chronic kidney disease progression among black patients attending a tertiary hospital in Johannesburg, South Africa

Abstract

Background: Chronic kidney disease (CKD) is a leading health issue and its magnitude has been increasing globally; where the developing countries are the most affected and they are the least equipped to deal with its associated consequences. Chronic kidney disease can rapidly and quietly progress to late CKD stages in impoverished environments. Early recognition of patients who are likely to develop end-stage kidney disease (ESKD) is important. Methodology: A prospective longitudinal study was conducted on CKD patients of black ethnicity attending at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) renal outpatient clinic in South Africa, as from September 2019 to March 2022. Patients provided blood and urine samples for investigations in the laboratory at study enrolment (0) and at the 24 months follow up. The concentrations of the transforming growth factor isoforms [(TGF)-β1, TGF-β2 and TGF-β3) were determined in serum and urine at baseline using the Human TGF-β duoset ELISA. Data were descriptively and inferentially processed by the REDcap and analyzed using STATA version 17 and multivariable logistic regression analysis was applied to find out the predictors of CKD progression. Results: A total of 312 patients were recruited into the study; the median age was 58 (IQR 46 -67) years and 162 (51.9 %) were male. Hypertension was present in majority (96.7 %) of the patients. Diabetes mellitus was present in 38.7 % of patients and 38.1 % of the study patients had both hypertension and diabetes mellitus. A total of 297 (95.2%) patients completed the study. Death was reported in 5 (1.6%) patients and 10 (3.2%) of patients were lost to follow up. The prevalence of CKD progression was 49.5%, 33% had CKD remission and 17.5% had CKD regression while the prevalence of CKD progression by change in uPCR > 30% was 51.9%. Almost half (47.8 %) had a sustained decline in eGFR of > 4 ml/min/1.73 m2 /year or more, 35.0% of the patients moved to a more severe stage of CKD and 19.9% had more than 30% 6 decline in eGFR in two years. For patients with CKD progression, 54.9% patients were men and at baseline, their median age was 59 (46 - 67) years, urine protein creatinine ratio (uPCR) increased at 0.039 (0.015-0.085) g/mmol, eGFR was 37 (32 -51) mL/min/1.73 m2; the median serum TGF-β1 was 21210 (15915 – 25745) ng/L and the median urine TGF-β3 was 17.5 (5.4 –76.2) ng/L. For those who had CKD progression, hypertension was present in the majority (95.2%) of the patients. Diabetes mellitus was present in 59 (40.1%) patients and 58 (39.5%) patients had both hypertension and diabetes mellitus; 48.3% had severely increased proteinuria, 45.6% patients had anaemia, 34.0% had hyperuricemia and 17.7% had hypocalcaemia at baseline. For those patients with CKD progression vs those without CKD progression, the baseline median serum TGF-β1 was 21210 (15915 – 25745) ng/L vs 24200 (17570 – 29560) ng/L, the baseline median urine TGF-β3 was 17.5 (5.4 – 76.2) ng/L vs 2.8 (1.8 – 15.3) ng/L; however, baseline serum and urine TGF-β isoforms did not predict progression of CKD on univariate and multivariable analyses. Regarding use of medications among patients with CKD progression, calcium channel blockers (amlodipine) were used by majority (85.2 %) of the patients. Diuretics were used by 63.4% of the patients and 31.7 % of the patients were using insulin. Variables associated with CKD progression after multivariable logistic regression analysis were moderately elevated proteinuria (OR 2.1, 95% CI (1.1 – 3.9), P= 0.019), severely elevated proteinuria (OR 6.1, 95 % CI (3.2 – 11.6), P = 0.001), hyponatraemia (OR 4.5, 95% CI 1.8 - 23.6, P= 0.042), hypocalcaemia (OR 3.8, 95 % CI 1.0 - 14.8, P = 0.047), anaemia (OR 2.1, 95% CI 1.0 - 4.3, P= 0.048), elevated HbA1c (OR 1.8, 95 % CI 1.2 - 2.8, P = 0.007), diabetes mellitus (OR 1.8, 95 % CI 1.9 - 3.6, P = 0.047), current smoking (OR 2.8, 95 % CI 1.9 - 8.6, P = 0.049), medications which were calcium channel blockers (OR 2.07, 95 % CI 1.04 – 4.12, P = 0.038), diuretics (OR 2.35, 95 % CI 1.37 – 4.00, P = 0.002), insulin (OR 1.96, 95 % CI 1.01 – 3.84, P = 0.048) and baseline serum calcium levels (OR 0.06, 95 % CI 0.01 -0.64, P = 0.019). An increase in uPCR > 30% at two years identified most patients with CKD progression; clinicians and nephrologists should utilize change in uPCR > 30% at two years to identify those patients with CKD who are likely to progress more rapidly, who require closer surveillance and monitoring with emphasis on slowing or stopping progression of the CKD. Conclusion: Our study has demonstrated a higher prevalence of CKD progression in a prospective longitudinal study among black patients than that reported in previous studies. CKD progression was associated with current smoking, hyponatremia, hypocalcemia, anaemia, elevated HbA1c, diabetes mellitus, and proteinuria. While patients with CKD progression had lower baseline concentrations of serum TGF-β1 and increased baseline urinary TGF-β3 concentrations, baseline serum and urine TGF-β isoforms did not predict progression of CKD. The roles of the various serum and urine TGF-β isoforms in CKD progression at baseline are still unclear and highlight the importance of further studies to determine their isoform specific effects.