Rising heat, failing kidneys: Heat stress nephropathy in climate crisis

Dehydration and hyperosmolarity

Dehydration from heat stress leads to decreased renal blood flow and increased blood osmolality. This activates vasopressin, which, while conserving water, can have deleterious effects on the kidney with chronic activation.¹² Hyperosmolarity drives the activation of the polyol-fructokinase pathway, leading to local oxidative stress and inflammation in the kidney.^13,14

Recurrent subclinical rhabdomyolysis

Strenuous physical labor in hot conditions can cause low-grade muscle breakdown, leading to myoglobin release, which can be nephrotoxic, especially in the dehydrated state.¹⁵ The repeated nature of this injury pattern may be particularly relevant in agricultural workers in South Asia who perform daily manual labor in extreme heat.

Uric acid crystal formation

Heat and dehydration produce concentrated, acidic urine, which promotes uric acid crystallization within the renal tubules.¹⁶ These crystals can cause tubular damage and inflammation. Hyperuricemia has been identified as a common finding in cases of HSN and may play a direct role in disease pathogenesis.^17,18

Inflammatory responses

Heat stress triggers the release of inflammatory mediators, including cytokines and chemokines, which leads to tubulointerstitial inflammation.¹⁹ This inflammatory response can result in progressive kidney damage with repeated exposure to heat stress.

Mitochondrial dysfunction

Heat stress causes intracellular calcium overload and mitochondrial dysfunction, resulting in decreased ATP production and increased oxidative stress.⁶ This cellular energy crisis contributes to tubular damage and may potentially lead to cell death.

Vascular endothelial dysfunction

Endothelial dysfunction with decreased nitric oxide production occurs in response to heat stress, leading to altered renal hemodynamics and potentially contributing to ischemic kidney injury.¹⁸

The chronic nature of these pathophysiological processes, with repeated subclinical kidney injuries over time, eventually leads to permanent kidney damage manifested as CKD.¹² This model of recurrent acute kidney injury (AKI) leading to CKD is increasingly recognized as central to the pathogenesis of HSN, as illustrated in Figure 1.

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Figure 1:

Pathophysiological pathway of HSN in South Asia. The diagram illustrates the complex interplay between environmental factors, physiological responses, and renal injury mechanisms that lead to the development of HSN, highlighting the central role of recurrent dehydration and heat exposure in disease progression. HSN: Heat stress nephropathy.

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India

In India, CKDu, characterized by similarities to Mesoamerican nephropathy has been reported from multiple states, including Andhra Pradesh, Tamil Nadu, Telangana, Puducherry, Chhattisgarh, Goa, and Odisha.^20,21 Coastal Andhra Pradesh has gained particular attention, with studies reporting a high prevalence of CKDu (~50%) among agricultural workers.^22,23 Similarly, concerning reports have emerged from hot coastal districts of Odisha.²⁴

Raju et al. documented that most cases of CKD are registered between March and May, a period associated with heatwaves.⁹ They also documented an increase in serum creatinine and blood urea along with age-related decline in eGFR in agricultural workers and construction labors.⁹ Clinical observations from the Purulia district of West Bengal suggest that CKDu is more common than CKD due to traditional causes (diabetes, hypertension, autoimmune diseases, and primary glomerulonephritis) among chronically dehydrated rural patients from areas with poor water supply. These CKDu cases often have a history of exposure to extreme heat during the summer months, particularly during heatwaves.²⁵

Kidney biopsies from the Uddanam region show tubulointerstitial disease and parenchymal fibrosis similar to findings in Mesoamerican nephropathy, supporting the role of heat stress in the pathogenesis of these cases.²³ However, biopsies are infrequently performed in this population due to limited healthcare access or advanced disease at presentation.

Sri Lanka

In the North Central Province of Sri Lanka, a high prevalence of CKDu has been documented since the late 1990s.⁵ The disease primarily affects rural farming communities working in hot conditions. Kidney biopsies from affected individuals show tubulointerstitial disease and progressive fibrosis, similar to findings in other hot regions globally.²⁶

The Sri Lankan nephropathy shares many clinical features with HSN, including minimal proteinuria, absence of hypertension in early stages, and a predominance in agricultural workers exposed to chronic heat stress and dehydration.²⁷ While agrochemicals have been proposed as potential contributors, the role of heat stress and recurrent dehydration is increasingly recognized.²⁷

Pakistan and Bangladesh

Although less extensively documented, reports of increased kidney disease in hot regions of Pakistan and Bangladesh have emerged, particularly following severe heatwaves. The 2015 heatwave in Karachi, Pakistan, resulted in over 1000 deaths, with a significant proportion of patients presenting with AKI.²⁸

Demographic and epidemiologic profile

HSN predominantly affects rural agricultural workers, particularly males aged 30–60 years who work in hot conditions with limited access to shade or adequate hydration.²¹ The condition shows a clear geographical distribution, with higher prevalence in coastal and hot inland regions. Studies from the Uddanam region of Andhra Pradesh report prevalence rates of 40%–60% among agricultural communities, significantly higher than the national average of 17.2% for traditional kidney diseases.^23,29 The male predominance (male-to-female ratio approximately 3:1) likely reflects occupational exposure patterns, as men are more frequently engaged in intense outdoor labor in South Asian agricultural settings.²³

Clinical presentation

The disease typically follows a biphasic pattern:²¹

• Early stage: Generally asymptomatic or characterized by non-specific symptoms including frequent episodes of heat-related illness during work (dizziness, muscle cramps, extreme fatigue), episodic low-grade fever, and intermittent flank pain. These symptoms are often dismissed as routine consequences of physical labor in hot conditions, which can lead to delayed diagnosis.

• Advanced stage: As kidney function deteriorates, patients develop classic symptoms of CKD, including persistent fatigue, loss of appetite, nausea, vomiting, pruritus, edema, and eventually signs of uremia. Notably, many patients report a history of recurrent AKI episodes during hot seasons that progressively failed to resolve completely.

Patients frequently describe a seasonal pattern to their symptoms, with exacerbations during summer months and periods of relative improvement during cooler seasons, creating a “sawtooth” pattern of declining kidney function that distinguishes HSN from other forms of CKD.¹

Laboratory and imaging findings

HSN presents with characteristic laboratory abnormalities:^{6,21,23,30,31}

• Urinary findings: Mild proteinuria (typically <1 g/day), which distinguishes it from diabetic nephropathy and other glomerular diseases where proteinuria is more pronounced. Urinalysis typically shows minimal or absent hematuria.

• Blood chemistry: Elevated serum creatinine and blood urea nitrogen, reflecting reduced kidney function. Hyperuricemia is notably common (70%–80% of patients), even in early stages of the disease, suggesting a potential role of uric acid in pathogenesis.

• Electrolyte abnormalities: Hypokalemia is frequently observed (50%–60% of cases), likely due to tubular dysfunction. Hypocalcemia and hypomagnesemia may also occur in advanced stages of the disease.

• Other markers: Studies from South Asian populations have reported altered markers of tubular injury, including elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, even in patients with relatively preserved glomerular filtration rates, suggesting early tubular damage.

• Imaging: Renal ultrasonography typically shows bilateral small kidneys with increased echogenicity in advanced cases, reflecting chronic renal parenchymal disease. Early cases may show kidneys of normal or slightly reduced size.

Histopathological features

Kidney biopsies from affected individuals in South Asia reveal distinctive pathological changes:^23,32

• Predominant tubulointerstitial disease: The hallmark finding is tubular atrophy and interstitial fibrosis with minimal glomerular involvement in early stages. Studies from the Uddanam region by Gowrishankar et al. showed that tubulointerstitial fibrosis affects 5%–85% of the renal parenchyma in advanced cases.³²

• Tubular changes: Tubular atrophy, tubular dilation, and thickening of tubular basement membranes are common. Proximal tubules exhibit loss of brush borders, indicative of chronic injury.

• Interstitial changes: Interstitial fibrosis is accompanied by mononuclear inflammatory cell infiltrates, primarily consisting of lymphocytes and macrophages.

• Vascular changes: Hyalinosis of small arterioles and thickening of vessel walls are frequently observed, potentially reflecting chronic ischemic changes.

• Glomerular changes: In early stages, glomeruli appear relatively preserved, with focal global glomerulosclerosis appearing in later stages (25%–80%), likely secondary to the tubulointerstitial damage.

Clinical course and disease progression

HSN typically follows a progressive course if exposure to heat stress continues and preventive measures are not implemented:^9,21,30

• Rate of progression: Without intervention, many patients experience gradual progression to end-stage renal disease, often within 3–5 years of diagnosis. The rate of GFR (glomerular filtration rate) decline appears to be faster (average 3–4 ml/minute/1.73 m²/year) than in many other forms of CKD.

• Treatment response: The condition shows a limited response to standard renoprotective medications, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, unlike diabetic or hypertensive nephropathy. However, early intervention with hydration strategies and reduction of heat exposure can significantly slow progression.

• Comorbidities: Unlike traditional forms of CKD, early-stage HSN patients typically lack hypertension or diabetes. Hypertension often develops later as a consequence rather than a cause of kidney damage. This pattern differs markedly from the common CKD profile in urban South Asian populations, where diabetes and hypertension predominate as etiological factors.

Distinguishing features from other forms of CKD

Several features help distinguish HSN from other forms of kidney disease in the South Asian context:

• The absence of traditional risk factors (diabetes, hypertension) in early stages.

• The geographical clustering in hot agricultural regions.

• The seasonal pattern of symptoms and disease exacerbation.

• The predominant tubulointerstitial pattern of injury on histopathology.

• The minimal proteinuria despite significant reduction in kidney function.

• The strong association with occupational heat exposure and dehydration.

The distinct clinical profile of HSN in South Asia, particularly its predominance in agricultural communities exposed to chronic heat stress, strongly suggests an environmental etiology related to occupational heat exposure and recurrent dehydration, potentially augmented by region-specific factors such as water quality, genetic susceptibility, and nutritional status.

Occupational factors

Agricultural work, which employs a significant proportion of the South Asian population, involves strenuous labor in hot conditions with limited access to shade, rest periods, or adequate hydration.³³ Construction workers, brick kiln workers, and those in glass and metal industries are similarly vulnerable due to high occupational heat exposure.³⁴

Climatic factors

South Asia’s hot and humid climate, with temperatures frequently exceeding 40°C during summer months, creates conditions where the body’s natural cooling mechanisms become insufficient.⁷ High humidity further impairs evaporative cooling, increasing the risk of hyperthermia.¹⁰

Water quality and availability

Limited access to clean drinking water is common in many rural areas of South Asia, contributing to chronic dehydration.⁶ Additionally, some regions report high silica and strontium content in drinking water, which may have nephrotoxic effects when consumed chronically by dehydrated individuals.³⁵

Socioeconomic factors

Poverty, limited education, and inadequate access to healthcare contribute to the delayed diagnosis and management of kidney injury.⁶ Economic necessities often force laborers to continue working despite symptoms of heat stress.

Hydration practices

Cultural hydration practices, including the consumption of sugary beverages for rehydration, may inadvertently worsen kidney injury.³⁶ Studies have shown that rehydration with fructose-containing beverages may exacerbate dehydration-induced kidney damage.³⁷

Genetic susceptibility

Potential genetic polymorphisms affecting heat tolerance and kidney susceptibility to injury may play a role, although this remains understudied in South Asian populations.³⁸

Potential environmental toxins

While heat stress and dehydration appear to be primary drivers, some researchers suggest that environmental toxins, including agrochemicals and heavy metals, may act as cofactors, particularly when concentrated in the dehydrated state.³⁹

Occupational interventions

1. Work scheduling modifications: Implementing early morning or evening work schedules during hot seasons to avoid peak heat.⁴⁰

2. Mandatory rest periods: Enforcing scheduled breaks, particularly during the hottest part of the day (e.g., limiting work to 15 minutes/hour during extreme heat).⁴¹

3. Shade provision: Establishing mobile shaded rest areas for agricultural and construction workers.⁴¹

4. Cooling techniques: Implement personal cooling strategies, including wearing appropriate clothing and utilizing cooling stations.⁴²

Hydration strategies

1. Scheduled hydration: Promoting regular water consumption (250 ml every 20 minutes) during work in hot conditions.⁴³

2. Water quality improvement: Ensuring access to clean drinking water and addressing potential contaminants in water sources

3. Appropriate rehydration solutions: Educating about proper hydration solutions and discouraging rehydration with sugary beverages.³⁷

Early detection and monitoring

1. Screening programs: Implementing community-based screening for early kidney dysfunction in high-risk populations.⁴⁴

2. Biomarker monitoring: Utilizing novel biomarkers for early detection of kidney injury before permanent damage occurs.⁴⁵

3. Heat alert systems: Developing heat warning systems tailored to local conditions to provide timely alerts during extreme heat events.⁴⁶

Policy and public health measures

1. Occupational safety regulations: Establishing and enforcing heat-exposure limits and mandatory rest periods for workers in hot conditions.⁴⁷

2. Heat action plans: Developing comprehensive heat action plans at national and local levels, incorporating kidney protection strategies.⁴⁸

3. Healthcare access: Enhancing access to healthcare services for early intervention in cases of AKI.

Educational initiatives

1. Worker education: Training workers on recognizing, preventing, and the importance of adequate hydration in relation to heat stress.

2. Healthcare provider awareness: Educating healthcare providers about HSN for improved diagnosis and management.

3. Community awareness: Raising public awareness about the kidney risks associated with heat exposure and chronic dehydration.

Pharmacological approaches

1. Uric acid management: Consider allopurinol or febuxostat for individuals with hyperuricemia to potentially reduce the progression of kidney injury.¹⁷

2. Electrolyte monitoring and replacement: Addressing electrolyte imbalances, particularly hypokalemia, which is common in HSN.⁴⁹

Climate adaptation strategies

1. Agricultural adaptations: Promoting climate-smart agricultural practices that reduce heat exposure.⁵⁰

2. Urban heat island mitigation: Implementing strategies to reduce urban heat islands through increased vegetation and reflective surfaces.⁵¹

3. Climate change mitigation: Supporting broader climate change mitigation efforts to reduce future temperature increases.⁵²

Management of early-stage HSN

For patients with early-stage HSN (estimated GFR >60 ml/minute/1.73 m²), the following approaches have shown benefit:

1. Occupational modification: The most crucial intervention is reducing heat exposure by changing work patterns, including transitioning to indoor work when possible or implementing significant modifications to outdoor work schedules.^1,40

2. Hydration protocol: Structured hydration regimens with consumption of 4–6 l of clean water daily, with emphasis on prehydration before work and scheduled drinking during work (typically 250 ml every 20–30 minutes during heat exposure). Studies in agricultural workers have demonstrated that supervised hydration programs can stabilize or even improve kidney function in early HSN.^43,53

3. Electrolyte management: Addressing hypokalemia through dietary modification (increased consumption of potassium-rich foods) or supplementation when necessary. Oral potassium supplementation may be required in 30%–40% of patients with persistent hypokalemia.^12,49

4. Uric acid reduction: Given the high prevalence of hyperuricemia in HSN patients, uric acid-lowering therapy with xanthine oxidase inhibitors (allopurinol or febuxostat) has demonstrated benefit in slowing the progression of kidney dysfunction. Studies suggest starting at lower doses (allopurinol 100 mg daily) with gradual escalation to avoid hypersensitivity reactions.^16,17

5. Urinary alkalization: Alkalization of urine may help prevent uric acid crystal formation in renal tubules; a mechanism proposed as one cause of injury in HSN. Sodium bicarbonate supplementation serves this purpose while also addressing metabolic acidosis commonly seen in tubulointerstitial diseases.^4,6

6. Anti-inflammatory approaches: Limited data suggest potential benefit from low-dose anti-inflammatory medications, though concerns about NSAID (non-steroidal anti inflammatory drug) nephrotoxicity necessitate caution.¹⁹ Recent small studies have explored pentoxifylline as an alternative anti-inflammatory approach with some promising preliminary results.⁵⁴

Management of advanced HSN

For patients with more advanced disease (eGFR <60 ml/minute/1.73 m²), additional interventions include:

1. Standard CKD care: Implementation of established CKD management protocols including blood pressure control, proteinuria reduction with ACE (angiotensin-converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) (even with modest proteinuria), and dietary protein moderation.²¹

2. Metabolic acidosis correction: Sodium bicarbonate supplementation to maintain serum bicarbonate >22 mEq/l, which may slow progression of kidney injury, particularly important given the tubular nature of HSN.¹⁷

3. Anemia management: Early intervention for anemia with iron supplementation and erythropoiesis-stimulating agents when appropriate, as anemia can worsen heat stress and exacerbate kidney hypoxia.¹

4. Cardiovascular risk reduction: Aggressive management of cardiovascular risk factors, as cardiovascular disease remains the leading cause of mortality in HSN patients, similar to other forms of CKD.⁴

Renal replacement therapy considerations

End-stage kidney disease from HSN presents several region-specific challenges:

1. Access barriers: The limited availability of dialysis facilities in rural areas, where HSN is most prevalent, creates significant barriers to care.⁵ Community-based peritoneal dialysis programs have shown promise in several South Asian regions as an alternative to center-based hemodialysis.⁵⁵

2. Transplantation challenges: While kidney transplantation offers the best long-term outcomes, limited transplant programs, cultural barriers, and high costs restrict access for most HSN patients. Developing regional transplant networks specifically targeting HSN-endemic areas could improve access.

3. Palliative approach: For patients without access to dialysis or transplantation, structured conservative care programs focusing on symptom management, quality of life, and psychosocial support are essential but remain underdeveloped in most affected regions.

Novel and investigational therapies

Several therapeutic approaches under investigation show potential for HSN:

1. Fructokinase inhibitors: Based on the role of the polyol-fructokinase pathway in HSN, inhibitors of this pathway are under preclinical investigation and may eventually provide targeted therapy.¹⁴

2. Bardoxolone methyl and other Nrf2 activators: These agents enhance cellular antioxidant capacity and have shown promise in other forms of CKD. Early studies in heat stress models suggest potential benefit.⁵⁶

3. Targeted anti-fibrotic therapies: Given the prominent interstitial fibrosis in HSN, anti-fibrotic approaches that have shown benefit in other kidney diseases are being explored.⁵⁷

4. Heat shock protein inducers: Pharmacological enhancement of heat shock protein expression, which can protect against heat-induced cellular damage, represents a novel approach currently in early-stage investigation.⁵⁸

The treatment of HSN requires a combination of targeted interventions addressing the unique pathophysiology of the disease alongside established approaches for managing CKD. The limited healthcare resources in many affected regions necessitate innovative, cost-effective approaches that can be implemented on large scale in rural settings. While current evidence supports several treatment strategies, ongoing research is crucial to develop more effective and targeted therapies for this climate-sensitive kidney disease.