RISK FACTOR ASSESSMENT AND HISTOPATHOLOGICAL EVALUATION OF PATIENTS WITH CKDU

Introduction:

CKDu is emerging as an important cause of CKD in India with a prevalence of 16% second only to diabetes 31.3%. This term CKDu was first used in El Salvador to describe a disease predominantly affecting agricultural communities. Later several parts of the world reported CKDu. It is important to understand the etiopathogenesis which will help in planning the preventive measures. Various hypotheses have been proposed in different geographical locations. These include heat stress, drinking water contamination especially with high silica and fluoride levels, pesticide exposure, herbal and native medicine intake, leptospirosis infection and other genetic factors.  There is paucity of data on the  epidemiology, clinical features, laboratory determinants and the histopathological parameters in CKDu in Telangana. Hence this study was undertaken to identify possible underlying risk factors and also to assess the kidney histology among CKDu patients

Methods:

This is a single center, prospective observational study conducted from March 2021 to November 2022 on CKD of undetermined origin (CKDu) patients presenting to a tertiary care institute in South India either as inpatients or outpatients. CKDu was defined as per the Indian consensus. 

Inclusion criteria

Mandatory criteria: eGFR less than 60 mL/min/1.73 m2 by CKD-EPI formula and/or urine protein 1 plus or more by dipstick

With USG showing small shrunken kidneys and/or kidney biopsy s/o chronic tubulointerstitial nephritis with absence of immune deposits

Exclusion criteria

Diabetes mellitus diagnosed by HbA1C >6.5% and FBS >126 mg/dL or patient on antidiabetic medications

Any BP more than 140/90 in stage 1, 2 CKD and BP >160/100 in stage 3, 4, 5 CKD or patient requiring two or more types of antihypertensive medications for BP control (4) 

CKD of known cause (such as obstruction, stones, vasculitis, lupus) 

Urine protein creatinine ratio >2 g/g 

Hematuria >5 red blood cells/HPF

Basic and specific investigations like complete hemogram, USG KUB, kidney function tests including urine protein estimation were done. Renal functions were assessed at 0, 6 and 12 months.

Whenever feasible kidney biopsy was performed, and the tissue was analyzed for light microscopic findings and immunofluorescence study.

Source of drinking water was noted. Surface water included water consumption from streams, lakes etc. while ground water was from bore well or municipal water. Drinking water analysis was done at baseline for all patients to screen for toxins and heavy metals in the drinking water that could have contributed to the development of CKDu. The analysis was performed at Institute of preventive medicine, Narayanaguda.

Kidney outcomes of these patients were analyzed in terms of rate of GFR decline in 1 year, need for Kidney replacement therapy and mortality. Fast progressors were defined by a fall of eGFR of ≥4ml/min/1.73 m2 progression and slow progressors by a fall of eGFR of <4ml/min/1.73m2 in a year. Progression to MHD or death were noted. Analyses were carried out to identify the possible risk factors for faster progression of the disease, need for RRT and death.

STATISTICAL METHODS

Descriptive and inferential statistical analysis were carried out. Continuous measurements were presented on Mean ± SD (Min-Max). Categorical data was represented as frequencies and percentages. Significance was assessed at 5 % level of significance. Chi square test was used as test of significance for categorical data.

Unpaired t test (for 2 groups) and ANOVA test (for more than 2 groups) were used as tests of significance for continuous data. Bar charts and pie charts were used for pictorial representation of data wherever possible. P value: <0.05 was considered significant. The Statistical software SPSS 22.0, and R environment ver.3.2.2 were used for the analysis of the data and Microsoft word and Excel was used to generate graphs, tables etc

Results:

Basic demographic profile and clinical characteristics are mentioned in the Table 1.

Majority of patients 52 (69%) were non- oliguric at presentation.21(28%) had a history of nocturia. Easy fatigability was seen in 58(77.3%). 30(40%) had history of alternative medicine use for varied indications like infertility, hemorrhoids, joint pains, etc. The duration of medicine varied from 2 months to a year. Oedema was seen only in 10(13.3%). 42.7% were from Hyderabad followed by 10% from Ranga Reddy district. Hyperuricemia was seen in 33%.

The results of drinking water analysis are as outlined in the table 2.

40% (n=30) of our patients at presentation had CKD5 while 9.3%(n=7) at presentation required RRT.

Among the 75 patients, 26 patients progressed to ESKD and required initiation of chronic dialysis. Among the 26 patients, 65.4% were males. 23.1% of patients in agriculture sector reached ESRD. 80.8% of those patients who progressed to CKD5D had consumed water from ground water (p value - 0.274). 42.3% of the patients had significant alcohol use while 26.9% of those who needed RRT had history of smoking. 53.8% of patients who needed MHD had developed hypertension during the course of disease. (p value - 0.281).

After excluding those who were lost to death or who needed MHD, it was found that total 28 patients had fast progression while 20 patients had slow progression of the CKD. Among the fast progressors, 75% were males, while 65% were males among the slow progressors (p value - 0.452). 28.6% of patients had agricultural background and 42.9% patients had hypertension among the fast progressors.

Kidney biopsy

Among the 35 biopsies that were performed on these patients, all had histopathological features of chronic interstitial nephritis. 54.3% (N=19) had > 50% global glomerulosclerosis. The severity of global glomerulosclerosis correlated poorly with serum creatinine (p value 0.616). Interstitial fibrosis and tubular atrophy >50% were present in 31.4% (N=11), 25-50% in 45.7%(N=16) and <25% (N=8). Serum creatinine correlated significantly with the IFTA (p value 0.002). This could be an indicator that the primary disease pathology is in the tubulointerstitial compartment rather than the glomerular compartment. Most patients presented with advanced chronicity at presentation.

Conclusions:

In conclusion, our study showed that CKDu in different parts of India is different from what is described in other parts of the world. Indian CKDu patients are relatively young, with male predominance and associated hypertension. Proteinuria even upto 2g/gm creatinine does not automatically rule out CKDu as many such patients had interstitial nephritis on biopsy. Our study highlights that agricultural background isn’t a necessity for development of CKDu in India. 40% patients presenting with CKD5 could indicate either these patients were diagnosed late or they could have been relatively asymptomatic in the initial stages. Finally, all kidney biopsies showing chronic interstitial nephritis emphasizes that primary pathology driving the disease process could be in the tubulointerstitial compartment and hence specific histopathological pointers towards CKDu should be looked for in the future biopsies including electron microscopy study as emphasized in the new position statement from ISN’s consortium on CKDu 

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.