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Chronic kidney disease of uncertain etiology (CKDu) is a term used to describe kidney disease without traditional risk factors.1Lunyera J. Mohottige D. von Isenburg M. Jeuland M. Patel U.D. Stanifer J.W. CKD of uncertain etiology: A systematic review.Clin J Am Soc Nephrol. 2016; 11: 379-385https://doi.org/10.2215/CJN.07500715Crossref PubMed Scopus (99) Google Scholar Disease clustering is reported from Central America, corresponding with the warmest areas along the Pacific coast and Srilanka.2Abraham G. Agarwal S.K. Gowrishankar S. Vijayan M. Chronic kidney disease of unknown etiology: hotspots in India and other Asian countries.Semin Nephrol. 2019; 39: 272-277https://doi.org/10.1016/j.semnephrol.2019.02.005Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar The Indian CKD registry reported CKDu as the second common cause of CKD in India, accounting for 16% of cases.3Rajapurkar M.M. John G.T. Kirpalani A.L. et al.What do we know about chronic kidney disease in India: first report of the Indian CKD Registry.BMC Nephrol. 2012; 13: 10https://doi.org/10.1186/1471-2369-13-10Crossref PubMed Scopus (224) Google Scholar We have described a new CKDu hotspot, Tondaimandalam nephropathy, from the northern coastal districts of Tamil Nadu, India.4Parameswaran S. Rinu P.K. Kar S.S. et al.A newly recognized endemic region of CKD of undetermined etiology (CKDu) in South India—"Tondaimandalam Nephropathy.".Kidney Int Rep. 2020; 5: 2066-2073https://doi.org/10.1016/j.ekir.2020.08.032Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The other CKDu hotspots from India include the Uddhanam, Andhra Pradesh, and Narsinghpur and Badamba blocks of Odisha.5Gummidi B. John O. Ghosh A. et al.A systematic study of the prevalence and risk factors of CKD in Uddanam, India.Kidney Int Rep. 2020; 5: 2246-2255https://doi.org/10.1016/j.ekir.2020.10.004Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,6Mahapatra H. Inamdar N. Chronic kidney diseases of unknown etiology (CKDu) hot spot at Narsinghpur and Badamba blocks in costal districts of Odisha, India.Indian J Nephrol. 2021; 31: 327-328https://doi.org/10.4103/ijn.ijn_56_20Crossref PubMed Google Scholar The changes in kidney function associated with seasons are often considered physiological and have not been extensively evaluated. We have undertaken a preliminary observational study to assess the changes in kidney function from the warmest to the coolest season of the year among prevalent CKDu patients with CKD stages 3 and 4. A total of 69 patients with CKDu were recruited. The summer and winter temperature and humidity were 41 °C (interquartile range 41–41) vs. 31 °C (interquartile range 31–31.75), and 56% vs. 74%, respectively. The baseline characteristics are given in Table 1. None of the patients progressed to end-stage kidney disease. Two patients developed acute kidney injury during the study period.Table 1Baseline characteristics at recruitment (March 2019)ParameterValueAgeaMedian with IQR., yr55 (48.5–61.5)Median prerecruitment follow-upaMedian with IQR., mo30 (15–35)Male-female ratio3.3:1Residence in a rural area, n (%)56 (81)Occupation, n (%) Agriculture12 (17) Outdoor manual work other than agriculture25 (36) Unemployed32 (46.3)Comorbidities, n (%) Hypertension33 (47.82) Hypothyroidism4 (5.80) Gout2 (2.90) CVA2 (2.90) CAD2 (2.90) Other comorbidities8 (11.60)RAAS blockade, n (%)5 (7.2)Uric acid–lowering agents, n (%)6 (8.6)CreatinineaMedian with IQR., mg/dl2.54 (2.16–3.04)eGFRbMean with 95% CI., ml/1.73 m225.9 (24.5, 28.6)Urine PC ratioaMedian with IQR., mg/g0.31 (0.18–0.68)Systolic blood pressureaMedian with IQR., mm Hg128 (110–140)Diastolic blood pressureaMedian with IQR., mm Hg80 (70–90)BMIbMean with 95% CI.23.7 (21.0, 25.5)Intact PTHaMedian with IQR., pg/ml115.3 (58.9–195.7)BicarbonateaMedian with IQR., mEq/l23.1 (22.2–23.9)pHbMean with 95% CI.7.37 (7.32, 7.40)Uric acidbMean with 95% CI., mg/dl8.06 (7.51, 8.62)BMI, body mass index; CAD, coronary artery disease; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; IQR, interquartile range; PC, protein-creatinine; PTH, parathyroid hormone; RAAS, renin-angiotensin-aldosterone system.a Median with IQR.b Mean with 95% CI. Open table in a new tab BMI, body mass index; CAD, coronary artery disease; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; IQR, interquartile range; PC, protein-creatinine; PTH, parathyroid hormone; RAAS, renin-angiotensin-aldosterone system. The changes in blood and urine parameters across the seasons are summarized in Table 2. The antihypertensive requirement increased from summer to winter (P = 0.020). The urine angiotensinogen-creatinine ratios showed a significant negative correlation with urine ammonium-creatinine ratios (Spearman ρ = –0.585 [summer, P < 0.001] and –0.786 [winter, P < 0.001]). Both stages 3 and 4 showed higher bicarbonate (P < 0.038) and urine ammonium-creatinine ratios in winter (P < 0.001); the urine angiotensinogen-creatinine ratios were higher in summer (P < 0.001) (Figure 1; Supplementary Table S1).Table 2Seasonal changes in kidney functionParameterSummerWinterP valueWeightaMean with 95% confidence interval., kg59.6 (57, 62.1)60 (57.3, 62.7).297Water intakebMedian with IQR., L2 (1–2.5)2 (1–2).713Systolic blood pressurebMedian with IQR., mm Hg129 (115–140)129 (118–142).923Diastolic blood pressurebMedian with IQR., mm Hg80 (70–89)79 (70–86).556Sodium bicarbonate dosebMedian with IQR., mg1500 (1000–1500)1500 (1000–1500).757Blood parameters OsmolaritybMedian with IQR., mOsm/kg290 (286–292)291 (285–295).076 SodiumbMedian with IQR., mEq/l138 (135–139)137 (135.5–139).457 PotassiumbMedian with IQR., mEq/l4.34 (3.81–4.78)4.38 (3.7–4.9).553 ChloridebMedian with IQR., mEq/l103 (99.5–105.5)102 (98.1–105).091 Uric acidaMean with 95% confidence interval., mg/dl8.4 (7.8, 8.9)7.8 (7.4, 8.3).041 pHbMedian with IQR.7.36 (7.32–7.36)7.36 (7.32–7.36).260 BicarbonatebMedian with IQR., mEq/l23.2 (21.7–25.5)25 (23–27).002 Bicarbonate <22 mEq/l, n (%)22 (31.9)13 (18.8).049 Base excessbMedian with IQR., mEq/l–0.9 (–4.5 to 1.6)0.1 (–2 to 1.9).026 Serum creatininebMedian with IQR., mg/dl2.73 (2.15–3.37)2.66 (2.16–3.33).247 eGFRbMedian with IQR., ml/min per 1.73 m223.60 (17.38–32.19)25.37 (17.57–31.65).161Urine parametersbMedian with IQR. Urine urea, mg/dl674 (525–908)733 (526–992).174 Urine osmolarity, mOsm/kg334 (278–441)354 (292–400).260 Urinary Na, mEq/l83 (64–104)84 (57–104).751 Urinary K, mEq/l28 (18–41)29 (20–41).741 Urine Cl, mEq/l83 (64–109)88 (62–107).673 Urine angiotensinogen (μg/L) / creatinine (mg/dl)30.1 (9.3–127)4.5 (2.8–8.8).002cAdjusted for proteinuria and eGFR. Urine ammonia (μmol/L) / creatinine (mg/dL)9.96 (7.00–17.01)21.03 (15.23–33.54)<.001cAdjusted for proteinuria and eGFR.eGFR, estimated glomerular filtration rate; IQR, interquartile range.a Mean with 95% confidence interval.b Median with IQR.c Adjusted for proteinuria and eGFR. Open table in a new tab eGFR, estimated glomerular filtration rate; IQR, interquartile range. We observed that summers were associated with more acidosis, higher uric acid levels, low urine ammonium excretion, and increased angiotensinogen levels without estimated glomerular filtration rate or osmolarity changes. A few small, single-center studies have reported seasonal changes in the glomerular filtration rate in healthy and hypertensive individuals without CKD.7Ephraim R.K.D. Asamoah C.A. Abaka-Yawson A. Kwadzokpui P.K. Adusei S. Climate change causes changes in biochemical markers of kidney disease.BMC Nephrol. 2020; 21: 542https://doi.org/10.1186/s12882-020-02186-wCrossref PubMed Scopus (2) Google Scholar,8Masugata H. Senda S. Inukai M. et al.Seasonal variation in estimated glomerular filtration rate based on serum creatinine levels in hypertensive patients.Tohoku J Exp Med. 2011; 224: 137-142https://doi.org/10.1620/tjem.224.137Crossref PubMed Scopus (18) Google Scholar To our knowledge, there are no previous publications on seasonal changes in subjects with prevalent CKDu. Even though there were no documented heat strokes, the participants are likely exposed to low levels of chronic heat exhaustion. Uric acid is generated during heat stress owing to nucleotide release from the muscles.9Dematte J.E. O'Mara K. Buescher J. et al.Near-fatal heat stroke during the 1995 heat wave in Chicago.Ann Intern Med. 1998; 129: 173-181https://doi.org/10.7326/0003-4819-129-3-199808010-00001Crossref PubMed Scopus (336) Google Scholar,S1 The subjects had higher uric acid levels in summer in this study, possibly a surrogate marker of ongoing heat stress. Exposure to an ambient temperature of 39.5 °C induces mitochondrial dysfunction and tubular inflammation without osmolarity or creatinine change.S2 Further increments in core temperature by another degree resulted in more pronounced differences, including increased osmolarity and creatinine. Both high–anion gap and non–anion gap acidosis have been described in the setting of heat stroke.9Dematte J.E. O'Mara K. Buescher J. et al.Near-fatal heat stroke during the 1995 heat wave in Chicago.Ann Intern Med. 1998; 129: 173-181https://doi.org/10.7326/0003-4819-129-3-199808010-00001Crossref PubMed Scopus (336) Google Scholar In the present study, the lower bicarbonate levels in summer were not compensated by urine ammonium excretion. In the acute Mesoamerican nephropathy, significant interstitial inflammation and elevated serum inflammatory markers in the absence of serum osmolarity changes has been reported.S3 Subclinical tubular damage may be occurring in the summer months, leading to abnormal tubular functions resulting in a lower ammonium excretion. A low urine ammonium excretion is an independent and better prognostic factor for CKD progression than venous bicarbonate levels.S4–S7 The low NH4+ excretion reflects a functional failure of the acid transporters in the tubule. The resultant shift in the NH4+-NH3 dissociation equilibrium leads to an increased tissue availability of NH3, enhancing the renal toxicity by activating complement pathways.S5,S6 Even though urine ammonium excretion has a better predictive value, the levels do not exhibit a linear relationship with venous bicarbonate, endogenous acid production, or glomerular filtration rate.S4 In the present study, urine ammonium levels did not correlate with venous pH or bicarbonate concentrations. We observed that urine angiotensinogen levels were higher in summer after adjustments for GFR and proteinuria. In nonproteinuric individuals, angiotensinogen appearing in the urine represents the intrarenal renin activation rather than the systemic levels. Metabolic acidosis is associated with increased intrarenal renin-angiotensin-aldosterone system activation to increase the acid excretion in kidneys.S8,S9 However, this does not translate to elevated H+ excretion in patients with CKD because of structural and functional kidney damage.S9,S10 Another potential reason might be uric acid–induced intraglomerular hypertension, which may activate the intrarenal renin-angiotensin-aldosterone system.1Lunyera J. Mohottige D. von Isenburg M. Jeuland M. Patel U.D. Stanifer J.W. CKD of uncertain etiology: A systematic review.Clin J Am Soc Nephrol. 2016; 11: 379-385https://doi.org/10.2215/CJN.07500715Crossref PubMed Scopus (99) Google Scholar,S9 Even though blood pressures were comparable between seasons, we observed that the antihypertensive requirements were higher in winter. The blood pressures tend to be lower in summer, more marked in lower latitudes, with more prolonged sun exposure.S11,S12 A decline of blood pressure in ESRD cohorts has been documented in the summer months without any appreciable changes in total fluid volume.S13,S14 Lower temperatures cause increased sympathetic activity and vasoconstriction, whereas vasodilatation occurs in the summer months, resulting in lower blood pressures. The strengths of the study include recruitment of prevalent CKDu patients with stable drug prescriptions and kidney function. There were no confounders, such as renin-angiotensin-aldosterone system blockers or other drugs, to account for acidosis and urinary angiotensinogen levels. However, we do not have data on the daily dietary acid load, lactate, muscle enzymes, or uric acid excretion. Likely, the observed changes might not be confined to CKDu alone; similar seasonal changes might be operational in kidney diseases resulting from etiologies and in the healthy population. There are no control arms, including these groups, which acts as a limitation. In conclusion, the findings from this study point toward the existence of a distinct influence of seasons on kidney function in CKDu, which needs further field studies with larger sample sizes, with controls. All the authors declared no competing interests. This study received funding from the Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India. All procedures performed in studies involving human participants were per the ethical standards of the Indian Council of Medical Research and the institution, at which the studies were conducted (IRB approval no: JIP/IEC/2018/382) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Download .pdf (.31 MB) Help with pdf files Supplementary File (PDF) Supplementary Material and Methods. Table S1. The seasonal changes across CKD stages 3 and 4 Supplementary References.

Seasonal Changes in Kidney Function in CKD of Uncertain Etiology