Urine Concentration Ability in Residents of CKDu Endemic Areas

Introduction

CKD of unknown origin (CKDu) mainly described in rural communities in specific areas of the world.¹ It develops in the absence of known CKD risk factors and the clinical presentation is consistent with the chronic tubulo-interstitial nephritis phenotype. The histological analysis of kidney tissue of patients with early endemic CKDu shows predominant involvement of the tubulo-interstitial component, dominated by interstitial fibrosis with or without interstitial inflammation, tubular atrophy, and glomerular sclerosis. CKDu hotspots in India have been described mainly from Andhra Pradesh, but recent reports have highlighted clusters in central India, including parts of Chhattisgarh and Odisha.^2-5 A primary environmental ideology has been considered to be responsible for CKDu, and it is widely believed that most individuals residing in the endemic area are at risk of developing the disease.

CKDu has an insidious onset, and most affected individuals do not develop symptoms until very later. Unlike other types of kidney disease, there are no early markers of kidney damage, like proteinuria. Being a tubulointerstitial disease, early manifestations of CKDu are likely to be tubular abnormalities before there is a clinically evident decrease in glomerular filtration rate (GFR).³ A variety of novel serum and urinary biomarkers of tubular injury, such as kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), and others, are being studied as early predictors of kidney damage. However, none of them have been validated in large studies.

Testing for tubular function, such as urinary concentrating ability, may be an alternative strategy to detect the risk of developing CKDu early, before a drop in GFR. Urinary concentration requires proper delivery of glomerular ultrafiltrate to the tubules, a well-functioning hypertonic medullary interstitium, a structurally intact counter-current mechanism, and normal water permeability of the collecting tubules in response to the anti-diuretic hormone (ADH). There is a wide variation in urine osmolality with respect to changes in water intake. However, following several hours of water restriction, such as that occurring overnight during sleep, urine osmolality increases to between 800 and 1200 mOsm/kg H₂O in those with intact concentrating ability.^6,7

We studied urinary concentration ability by measuring fasting urine osmolality in the family members of patients with CKDu visiting AIIMS Raipur.

Materials and Methods

This cross-sectional study was conducted at the All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, between June 2021 and May 2022. The center has previously reported clustering of cases of CKDu in the Balangir and Nuapada districts of Odisha and Gariyaband and Mahasamund districts of Chhattisgarh.⁵ The study was approved by the Institutional Ethics Committee, AIIMS Raipur (AIIMS RPR/IEC/2021/723).

The study included adults >18 years who had resided in endemic areas for at least 10 years and were related to patients with CKDu admitted to the Department of Nephrology.

CKDu was defined according to standard criteria.^3,5 The accompanying relatives should have been residing in the same village as the index patient for at least the past 10 years. Individuals with known kidney disease, hypertension, diabetes, and a history of AKI, and urinary tract infection (UTI) were excluded.

Sociodemographic, clinical, and laboratory data were obtained via interviews and recorded in a structured proforma. The following laboratory tests were conducted: serum urea, creatinine, serum sodium, potassium, chloride, uric acid, random blood sugar, urine protein creatinine ratio, urinalysis including microscopy, and fasting plasma and urine osmolality. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation for non-blacks.

Results

A total of 108 patients with CKDu were admitted to the hospital during the study [Figure 1]. They had 150 accompanying relatives, of whom 102 (72%) consented to participate. Six participants were excluded: four because they had resided in the endemic area for <10 years, and two were hypertensive. Ninety-six participants underwent biochemical and fasting plasma and urine osmolality tests. Two participants were found to have eGFR <90 mL/min/1.73m², and one was found to be diabetic on investigations and was also excluded from the study, leaving 93 for final analysis [Figure 1].

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Figure 1:

Flow of the study.

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The median age of participants was 35 (IQR: 28, 46) years, and 60% were male (n=56). The median duration of stay in the endemic area was 34 (IQR: 28, 45) years [Table 1]. Most of the participants were offspring (n=45, 48.4%), spouses (n=20, 21.5%), or siblings (n=14, 15.1%) of patients with CKDu. The mean BMI of the participants was 20.9 ± 2.4 kg/m². The median systolic and diastolic blood pressures were 106 (IQR: 100, 110) and 68 (IQR: 60-70) mm Hg, respectively. The median eGFR of the participants was 105 (IQR: 95, 116.5) mL/min/1.73m^1, and the median urine protein creatinine ratio was 0.02 (IQR: 0.01, 0.05). Forty-three (46.2%) participants had hypokalemia (serum potassium < 3.5meq/L), 15 (16.1%) had hyponatremia (serum sodium <135 meq/L), and 14 (15.1%) had hypochloremia (serum chloride <96 meq/L).

The median fasting plasma osmolality was 290 (286, 294) mOsm/kg H₂O, and the median fasting Urine Osmolality was 620 (484, 850) mOsm/kg H₂O. Forty-six (49.5%) participants had fasting urine osmolality ≤600 mOsm/kg H₂O, 23 (24.7%) between 601 and 800 mOsm/kg H₂O, and 24 (25.8%) had urine osmolality >800 mOsm/kg H₂O. None of the epidemiological, clinical, and laboratory characteristics were significantly different between participants with fasting urine osmolality <600 mOsm/kg H₂O and those with >600 mOsm/kg H₂O [Supplementary Table 1].

Discussion

In this first-of-its-kind study, we show impaired urinary concentrating ability in about half of asymptomatic individuals with normal kidney function who are related to and reside in the same geographic area as individuals with established CKDu. This finding points to the possible subclinical involvement of the tubule-interstitial compartment in these individuals and supports the hypothesis that the insult that leads to the development of this condition is primarily directed towards this part of the kidney parenchyma.

CKDu has an insidious onset and is difficult to pinpoint. Clinical manifestation begins only after significant and irreversible permanent damage to the kidneys. Our findings suggest that this simple and widely available test can be used to screen individuals at risk of developing CKDu.

Patients with CKDu presenting to our center are agricultural workers from Gariyabandh and Mahasamund districts of Chhattisgarh and Balangir, Nuapada, and Kalahandi districts of Odisha. The clinical profile and renal histopathology in the affected people, and the highlighted delayed presentation to tertiary centers, have already been documented. A large proportion of these patients needed kidney replacement therapy at presentation.^4,5,8 This highlights the need for a simple test that can identify early stages, and the risk of developing the disease, so that appropriate interventions can be targeted. Serum creatinine-based eGFR is the traditional measure of kidney function, but its interpretation in early stages is open to debate. For example, an eGFR of 92 mL/min/1.73m² is considered within ‘normal’ range but may indicate a substantial decline of kidney function in a 25-year-old.

While many biomarkers are being studied as an early detection tool for CKDu, physiological tests of tubular functions, like urine concentration ability tests measured by fasting urine osmolality, might offer an alternative strategy to detect this disease. Normal individuals should be able to concentrate the urine to >850 mOsm/kg H₂O water after 12 hours of water deprivation.⁹ We hypothesized that the residents of the same villages might exhibit an alteration in urine concentrating ability. Given that such studies are challenging to conduct in the community setting due to social and logistical challenges, we approached caregivers (relatives) accompanying patients with CKDu admitted to our center, with the assumption that they would likely be exposed to similar environmental and genetic factors as those of patients with CKDu and therefore exhibit early pathophysiological changes.

Tabibzadeh et al.⁶ have described an independent relationship between fasting urine osmolality and GFR decline rate. The prevalence of impaired concentrating ability, defined as a fasting urinary osmolality value <600 mOsm/kg H₂O in stage 1 CKD patients in their cohort, was just 14% compared to almost 50% in our cohort of healthy individuals from the endemic area. It is further interesting to note that many participants also had electrolyte imbalances, including hypokalemia, hyponatremia, and hypochloremia. These electrolyte abnormalities may further indicate tubular dysfunction in these otherwise healthy participants.

A rigorous definition of CKDu, longer residence of the participants in the endemic area, and supervised fasting urine osmolality measurement are some of the strengths of our study. The study had certain limitations. Urine osmolality is mainly dependent on the diet of the participant, and maximal urinary concentrating ability typically involves 24 hours of water deprivation. The lack of normative data also makes the interpretation difficult. Further, animal studies have shown that the fasting state is associated with downregulation of Aquaporin2, which may itself confound fasting urine osmolality.¹⁰ Given that these participants were related to the index cases with CKDu and lived in the same locality, we cannot distinguish the impact of genetics from environmental insult on the development of kidney disease. Further, although we do demonstrate impaired concentrating function, long-term follow-up is required to see whether these individuals will indeed go on to develop CKDu if they do not alter their behavior.

To conclude, about 50% of seemingly healthy participants from the endemic belt of CKDu visiting AIIMS Raipur have low mean fasting urine osmolality after 12-hour overnight water deprivation, suggesting impaired urine concentrating ability and a larger at-risk population. Ours is a hypothesis-generating work, and further studies are needed to elucidate whether impaired urine concentrating ability signifies the early sign of underlying kidney disease and can predict the fall in GFR early.