Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome.

Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFß1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.

Macrophage polarization in kidney transplant patients.

BACKGROUND: Macrophages can oscillate between two functionally distinct states: proinflammatory M1 and anti-inflammatory M2. Classically- activated M1 macrophages produce proinflammatory cytokines (TNF-α, IFN-Æ´, and IL-6), which ares associated with graft dysfunction/rejections. In contrast, alternatively-activated macrophages M2 produce anti-inflammatory cytokines (IL-10) that are involved in host defense, tissue repair/remodeling, debris scavenging, and immune regulation, thereby helps to improve long-term graft survival. METHODS: In this study, we have identified graft dysfunction or rejection by biopsies using immunohistochemistry. Flow cytometry was used to detect M1 (CD163+, CD206+, and CD200R+) and M2 (CD86+, CD80+, and CD68+) macrophages. Enzyme-linked immunosorbent assay (ELISA) was used to measure a panel of cytokines. RESULTS: Histological analysis of the kidney transplants (n = 30) was used to distinguish those with acute/chronic allograft rejection (n = 15) from those with stable kidney function (n = 15). Flow cytometry results showed that patients with graft rejection exhibited macrophages with decreased expression (33.28%) of M2 macrophage markers (CD163+, CD206+, and CD200R+) and reduced production of IL-10 (as detected using ELISA). However, 71.33% of the macrophages were found to have M1 markers (CD86+, CD80+, and CD68+; p = 0.002) and produced proinflammatory cytokines (TNF-α, IFN-Æ´, and IL-6) by ELISA (p = 0.001) when compared with the healthy control group. In contrast, stable kidney transplants had 65.58% M2 and 27.66% M1 macrophages (p = 0.03) and produced IL-10. These findings suggest that M1 macrophages dominate in kidney grafts with dysfunction or rejection, whereas M2 macrophages dominate in kidney grafts with stable function. CONCLUSION: Our observations implicate a major shift towards M2 macrophages in stable kidney transplants, which are markedly downregulated in patients with graft dysfunction or rejection. In contrast, an increased frequency of M1 macrophages remained dominant in the pathophysiology of kidney transplants undergoing active dysfunction or rejection.

Effect of regulatory T cells on short-term graft outcome in kidney transplant recipients, a prospective observational, single-center study.

BACKGROUND: Regulatory T cells (Tregs) are important for maintaining immune homeostasis, limiting kidney transplant rejection, and promoting transplant tolerance. Tregs are characterized as CD4 + CD25+ T cells and the transcription factor Foxp3; they constitute 5-10% of all peripheral CD4+ T cells in healthy humans. The reduction in Treg cells after transplantation may be a predictive factor in graft rejection. Therefore, in this study, we investigated the association between Tregs and short-term graft outcomes in renal transplant recipients. METHODS: This prospective observational study included 50 patients of both sexes, aged between 18 and 60 years, with end-stage renal disease (ESRD), and who underwent kidney transplantation at the Nizams Institute of Medical Sciences. Flow cytometry was used to measure the percentage of Tregs (CD4 + CD25+) pre-transplant (baseline) and monthly post-transplant in 50 transplant recipients and 20 healthy controls (HC) over six months. The correlation between Treg percentages and graft outcomes was analyzed. RESULTS: The percentage of Tregs (Treg%) was significantly lower in ESRD patients before transplantation (baseline) than in the HCs [median 8.5% vs. 14.25%; p < 0.01]. After transplantation, Treg% decreased significantly within a week after grafting compared to the baseline pre-transplant level [median 5.13% vs. 8.5%; p < 0.01]. Moreover, Treg% was lower in the older (> 40 years) than that in the younger age group at one week after transplantation (p > 0.001). Treg% (CD4 + CD25+) was significantly lower in patients with deceased donor renal transplantation (DDRT) than in live renal transplantation (LRT) within the first week of transplantation [median 2.16% vs. 4.6%; p < 0.05] and at the time of graft rejection [median 3.2% vs. 9.2%; p < 0.001]. Induction therapy with anti-IL-2 receptor monoclonal antibody (IL-2RB) lowered Tregs to a greater extent than anti-thymoglobulin (ATG) therapy and no induction therapy [median 3.22% vs. 5.47%, 8.4%, p < 0.05]. In contrast, an increased Treg% was observed in transplant recipients with normal kidney graft function within six months after transplantation compared with the pre-transplant baseline level [median 11.54% vs. 8.5; p < 0.001]. ROC analysis of graft rejection resulted in an area under the curve (AUC) of 0.8 with a p-value <0.05. CONCLUSION: Within the first week after transplantation, the percentage of pre-transplant Tregs was significantly decreased compared to that in age- and sex-matched HC. The percentage of Tregs was also lower in patients with advanced age, DDRT, and those who received IL-2RB induction therapy. Patients who experienced graft rejection had lower Treg% compared to their pre-transplant levels. In contrast, patients with normal graft function at six months showed increased Treg%. Together, these results suggest that Treg% measurements are correlated with clinical outcomes.

Inhaled silica nanoparticles cause chronic kidney disease in rats.

Silica nanoparticles (SiNPs) released during the burning of sugarcane have been postulated to have a role in chronic kidney disease of unknown etiology. We tested the hypothesis that pristine SiNPs of the size present in sugarcane might cause chronic kidney injury when administered through the lung in rats. We administered 200- or 300-nm amorphous SiNPs twice weekly (4 mg/dose), or vehicle by oropharyngeal aspiration for 13 wk to rats followed by euthanasia after an additional 13 wk (26 wk total). Tissues were evaluated for the presence of SiNPs and evidence of histological injury. Both sizes of SiNPs caused kidney damage, with early tubular injury and inflammation (at week 13) that continued to inflammation and chronic fibrosis at week 26 despite discontinuation of the SiNP administration. Both sizes of SiNPs caused local inflammation in the lung and kidney and were detected in the serum and urine at week 13, and the 200-nm particles were also localized to the kidney with no evidence of retention of the 300-nm particles. At week 26, there was some clearance of the 200-nm silica from the kidneys, and urinary levels of SiNPs were reduced but still significant in both 200- and 300 nm-exposed rats. In conclusion, inhaled SiNPs cause chronic kidney injury that progresses despite stopping the SiNP administration. These findings support the hypothesis that human exposure to amorphous silica nanoparticles found in burned sugarcane fields could have a participatory role in chronic kidney disease of unknown etiology.NEW & NOTEWORTHY Inhalation of silica nanoparticles (SiNPs) released during the burning of sugarcane has been postulated to have a role in chronic kidney disease of unknown etiology (CKDu). We administered 200- and 300-nm amorphous SiNPs to rats by aspiration and observed kidney damage with tubular injury and inflammation that persisted even after stopping the SiNP exposure. These findings support the hypothesis that human exposure to SiNPs found in sugarcane ash could have a participatory role CKDu.

Revisiting Vasculopathy in Lupus Nephritis: A Renal Biopsy Evaluation Study.

Introduction: The classification of lupus nephritis (LN) on biopsy is essentially focused on morphologic changes in glomeruli. Renal vascular lesions are not addressed in detail in current classifications and are often overlooked. We aimed to determine the prevalence of vascular lesions in LN on biopsies and to compare these with biopsies not showing the vasculopathies. Methods: A total of 740 renal biopsies of LN were analysedfor presence of vasculopathies from January 2013 to June 2019. Of these, 527 (71.2%) biopsies showed vascular lesions (vascular group), which were further categorized into known five subtypes according to morphology and immunofluorescence (IF) findings. Remaining 213 (28.8%) biopsies constituted non-vascular group. Clinical, demographic and laboratory parameters were compared between these two groups. Results: The mean age was 27.95 ± 9.8 years and 27.0 ± 9.4 years in the vascular and non-vascular groups respectively with higher M:F (1:2 > 1:7) in vascular group. Majority of vasculopathies (257, 48.7%) were found in biopsies with class IV LN. Haematuria (69.8% vs. 20.1%), proteinuria (100% vs. 62%), anemia (48.3% vs. 3.60%) and hypertension (39.8% vs. 8.46%) were common in group I. Uncomplicated vascular immune deposits (426; 80.8%) were the most common vasculopathy and true vasculitis (4;0.8%) was least common. Activity and chronicity indices (7.35 ± 3 and 2.45 ± 1.5, respectively) were significantly higher in the vascular group. Activity index was highest in uncomplicated vascular immune deposits (7.45 ± 2.8) and chronicity index was highest in non-specific sclerotic vascular lesions (2.7 ± 1.6). Conclusion: Vascular involvement is common in LN. Uncomplicated vascular immune deposits were common vasculopathies whereas true vasculitis was least common. The morphology and IF both need to be carefully screened for the diagnosis of vasculopathies.

Neglected Trivial Trauma - A Cause for Pseudo-acute Kidney Injury.

Rupture of the urinary bladder and extravasation of urine into the peritoneal cavity leading to urinary ascites is an uncommon event, usually caused by blunt trauma to the abdomen. A high index of suspicion is required for early accurate diagnosis, which avoids unnecessary investigations and interventions. The disappearance of ascites following indwelling Foley's catheterization and high peritoneal fluid urea and creatinine compared to serum values are keys for diagnosis. Sometimes, the diagnosis may be delayed as the features are mistaken for intrinsic renal disease. Here, we report a case of pseudo-acute kidney injury caused by urinary ascites due to intraperitoneal bladder rupture following blunt abdominal trauma in an alcoholic patient.

A Case of Joubert Syndrome with Chronic Kidney Disease.

Joubert syndrome is a genetically heterogeneous disorder that belongs to the group of cerebello-oculo-renal syndromes. It is characterised by neurodevelopmental abnormalities and complex midbrain-hindbrain malformation, visible on brain imaging as a molar tooth sign. It is classified as a ciliopathy and has variable renal involvement. Herein, we report a case of a 9-year-old boy with developmental delay, presented as chronic kidney disease and evaluation showed features of Joubert syndrome. Recognition of specific clinical and radiological findings will help in early diagnosis and appropriate care.

Correlation between the clinical remission and histological remission in repeat biopsy findings of quiescent proliferative lupus nephritis.

BACKGROUND: The optimal duration of maintenance therapy is controversial in proliferative lupus nephritis (LN). Discordance between clinical parameters of renal remission and histological findings has made repeat biopsy a compulsory tool to confirm the histological remission (HR), but the timing is debatable. Aim of this study was to find the correlation of sustained complete clinical remission (CR) in sever lupus nephritis with histological findings on repeat kidney biopsy and appropriate duration of treatment in maintenance phase after achieving complete clinical remission. METHODS: Repeated kidney biopsy (biopsy 2) was performed on patients of biopsy proven (biopsy 1) proliferative LN who had been in CR for at least 2-years. The clinical and histologic findings of these groups (biopsy 1 and biopsy 2) were compared. Total 29 patients were included for the final analysis. Group 2 was further divided as per the duration of sustained CR (>48 months & <48 months). Regression analysis were used to find predictors of the HR. RESULTS: Average time taken to achieve CR was 9(range 2-24) months. Average duration of follow up and maintenance therapy was 68 ± 17.8 and 62.5 ± 14.2 months respectively. In the repeat kidney biopsy, HR was observed in 93.1% patients. Immunofluorescence study (IF) was normal in 72% of the patients. Normal light microscopy (LM) findings were observed in 58% patients. Transformation from proliferative to nonproliferative LN was noted in 82% cases. Other than the duration of CR on maintenance therapy and blood pressure, rest of the variables failed to predict HR. In sustained remission for more than 48-months group, 100% patients achieved HR whereas only 84% in 24-48-months group. CONCLUSION: Sustained CR on maintenance immunosuppressive therapy for more than 48-months duration predicts HR in repeat kidney biopsy findings in quiescent proliferative LN. Hence the minimum duration of maintenance therapy in proliferative LN should be at least for another 48 months after achieving CR.

Acute Kidney Injury and Nephrotic Syndrome in Guillain-Barre Syndrome: A Rare Clinical Scenario.

Guillain-Barre syndrome (GBS) is an acute polyradiculoneuropathy, caused by dysregulated immune response following an infectious or noninfectious event. Although cardiovascular, respiratory, and gastrointestinal systems are commonly involved secondary to neuromuscular paralysis, renal manifestations are rare. Acute kidney injury (AKI) can develop in GBS due to acute tubular necrosis secondary to dysautonomia. Minimal change nephrotic syndrome in GBS may be due to T-cell dysregulation and cytokine release attributed to molecular mimicry. Here, we report the case of GBS with simultaneously developed AKI and nephrotic syndrome during the course of disease, which recovered completely in parallel with neurological improvement without any immunosuppressive medications.

Chronic Kidney Disease of Unknown Etiology: Case Definition for India - A Perspective.

Chronic kidney disease of unknown etiology (CKDu) is a form of chronic kidney disease (CKD) that is prevalent in certain rural populations around the world. It is distinct by its clinicopathologic characteristics and has multifactorial etiology, being mostly linked to several environmental toxins. Although the presentation is similar in various regions across the globe, it also differs in subtle ways from region to region. In India too, there have been reports of the disease in several pockets. There is a need for a comprehensive definition to identify the cases accurately to ease clinical diagnosis and facilitate screening of populations in affected areas. This article presents the diagnostic criteria for CKDu proposed in a consensus meeting at Chennai, India, in May 2017.

A randomized, double-blind, positive-controlled, prospective, dose-response clinical study to evaluate the efficacy and tolerability of an aqueous extract of Terminalia bellerica in lowering uric acid and creatinine levels in chronic kidney disease subjects with hyperuricemia.

BACKGROUND: Hyperuricemia is an independent risk factor in chronic kidney disease (CKD). Allopurinol and febuxostat are prescription medicines used to treat hyperuricemia but suffer side-effects. Earlier clinical study has shown that an aqueous extract of Terminalia bellerica (TBE), significantly reduced uric acid levels with no serious adverse effects in hyperuricemic subjects. The objective of this study is to determine the efficacy and tolerability of TB in reducing uric acid and creatinine levels in CKD subjects. METHODS: 59-subjects were randomized to three groups-40 mg-once-daily febuxostat, 500 mg-twice-daily and 1000 mg-twice-daily of TBE. Serum uric acid, creatinine levels and estimated-glometular-filtration-rate were measured at baseline, 4, 8, 12, 16, 20, 24-weeks. Biomarkers of oxidative-stress, endothelial function, systemic inflammation, and platelet-aggregation were evaluated at baseline, 4, 8, 12, 24-weeks. Adverse drug reactions were recorded. Statistical analysis evaluated using GraphPadPrism4. RESULTS: 55-subjects completed 24-week study. Starting at 4-weeks, all treatment groups showed a significant decrease in serum uric acid levels from baseline (p ≤ 0.0001). At 24-weeks, febuxostat, T.bellerica 500 mg-twice-daily, and T.bellerica 1000 mg-twice-daily doses decreased mean-percentage serum uric acid by 63.70 ± 4.62, 19.84 ± 6.43 and 33.88% ± 4.95% respectively (p ≤ 0.0001). Significant decrease in serum creatinine with all the groups starting at 16-weeks was seen (p ≤ 0.005-p ≤ 0.0001). At 24-weeks, the mean-percentage change in creatinine levels was 23.71 ± 12.50, 11.70 ± 9.0, and 24.42 ± 8.14, respectively with febuxostat, T.bellerica 500 mg-twice-daily and T.bellerica 1000 mg-twice-daily. Statistically significant (p ≤ 0.05) increase in estimated glomerular filtration rate-(eGFR) was seen at 20 (p ≤ 0.05) and 24-weeks (p ≤ 0.01) for both febuxostat vs T.bellerica 500 mg-twice-daily and T.bellerica 1000 mg-twice-daily vs T.bellerica 500 mg-twice-daily. There was no statistically significant difference between febuxostat and T.bellerica 1000 mg-twice-daily, with an increase of eGFR of 41.38 and 40.39 ml/min/1.73m2 respectively, with the inference that T.bellerica at 1000 mg-twice-daily dose is as good as febuxostat 40 mg-once-daily. Positive improvements were made by all the groups in endothelial function and the related biomarkers and high-sensitivity C-reactive protein. None of the products showed effect on platelet aggregation. CONCLUSION: In this 24-week study Febuxostat 40 mg, T. bellerica 500 mg-twice-daily and 1000 mg-twice-daily, significantly decreased the serum uric acid and creatinine levels, increased eGFR in CKD subjects. T. bellerica 500 mg-twice-daily and 1000 mg-twice-daily were one-third and more than half as effective at 24-weeks, respectively. T. bellerica extract may be considered a natural alternative for reducing serum uric acid levels. TRIAL REGISTRATION: This study was registered with the Clinical Trials Registry - India (CTRI) with the registration number: CTRI/2019/11/022093 [Registered on: 21/11/2019] Trial Registered Retrospectively.

Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis.

Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of Twist1 (which encodes Twist) or Snai1 (which encodes Snail) in VE-cadherin+ or Tie1+ endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial cross-talk in the development of kidney fibrosis with a potential for therapeutic intervention.

Anti-glomerular basement membrane disease: A clinicomorphological study of 16 cases.

INTRODUCTION: Antiglomerular basement membrane disease manifests as rapidly progressive glomerulonephritis and alveolar hemorrhage. It encompasses 10-15% of crescentic glomerulonephritis and is associated with poor outcome. In this study, we have elaborated on the clinical details, morphological features, and outcome of anti-GBM glomerulonephritis. MATERIALS AND METHODS: All the consecutive biopsy-proven cases of anti-GBM glomerulonephritis over a period of 4½ years were analyzed, retrospectively. RESULTS: Sixteen cases were diagnosed as anti-GBM glomerulonephritis during the study period. Twelve patients presented with rapidly progressive renal failure of which four patients required hemodialysis at the time of presentation. Goodpasture's syndrome was noted in two patients. Thirteen cases were positive for circulating anti-GBM antibodies and two patients showed double positivity for both anti-GBM antibodies and ANCA. Fifteen biopsies revealed crescentic glomerulonephritis with linear deposition of IgG along the glomerular basement membrane in all the 16 cases. CONCLUSION: Renal biopsy analysis is important in the diagnosis of Anti GBM nephritis. Morphology is an important predictor of disease progression.

Isolated Vascular Lesions (IVL) in Early Allograft Biopsies: A Case Series.

This case series includes five patients diagnosed as isolated vascular lesion (IVL) on allograft biopsy in an early post-transplant period. These patients presented with graft dysfunction. The biopsies satisfied the criteria for IVL as laid down by Banff 2009. Four of these patients were treated with corticosteroids and other anti rejection measures. C4d and DSA were negative in all. The patients showed good response to treatment with stable graft function at the longest follow-up of one year. We have also reviewed the literature about IVL as a specific entity. There are differences between the molecular and clinical data of IVL. It is difficult to differentiate whether IVL is a rejection or non-rejection process. This study aims to highlight the importance of a rare entity.

Revisiting renal amyloidosis with clinicopathological characteristics, grading, and scoring: A single-institutional experience.

INTRODUCTION: Kidney involvement is a major cause of mortality in systemic amyloidosis. Glomerulus is the most common site of deposition in renal amyloidosis, and nephrotic syndrome is the most common presentation. Distinction between AA and AL is done using immunofluorescence (IF) and immunohistochemistry (IHC). Renal biopsy helps in diagnosis and also predicting the clinical course by applying scoring and grading to the biopsy findings. MATERIALS AND METHODS: The study includes all cases of biopsy-proven renal amyloidosis from January 2008 to May 2017. Light microscopic analysis; Congo red with polarization; IF; IHC for Amyloid A, kappa, and lambda; and bone marrow evaluation were done. Classification of glomerular amyloid deposition and scoring and grading are done as per the guidelines of Sen S et al. RESULTS: There are 40 cases of biopsy-proven renal amyloidosis with 12 primary and 23 secondary cases. Mean age at presentation was 42.5 years. Edema was the most common presenting feature. Secondary amyloidosis cases were predominant. Tuberculosis was the most common secondary cause. Multiple myeloma was detected in four primary cases. Grading of renal biopsy features showed a good correlation with the class of glomerular involvement. CONCLUSION: Clinical history, IF, and IHC are essential in amyloid typing. Grading helps provide a subtle guide regarding the severity of disease in the background of a wide range of morphological features and biochemical values. Typing of amyloid is also essential for choosing the appropriate treatment.

A randomized, double-blind, placebo-, and positive-controlled clinical pilot study to evaluate the efficacy and tolerability of standardized aqueous extracts of Terminalia chebula and Terminalia bellerica in subjects with hyperuricemia.

OBJECTIVES: To evaluate the efficacy and tolerability of standardized aqueous extracts of Terminalia chebula and Terminalia bellerica versus febuxostat and placebo on reduction in serum uric acid levels in subjects with hyperuricemia. MATERIALS AND METHODS: A total of 110 eligible subjects with hyperuricemia were enrolled and randomized to either of the five treatment groups - T. chebula 500 mg twice a day (BID), T. bellerica 250 mg BID, T. bellerica 500 mg BID, placebo BID, and febuxostat 40 mg once daily plus an identical placebo - for a duration of 24 weeks. Serum uric acid levels were measured at baseline and at the end of 4, 8, 12, 16, 20, and 24 weeks. Statistical analysis was done using GraphPad Prism Software 4. RESULTS AND INTERPRETATION: All active treatment groups showed a reduction in serum uric acid levels compared to baseline and placebo. Significant reduction in mean serum uric acid levels started as early as 4 weeks following treatment, compared to baseline, with T. bellerica (500 and 250 mg), febuxostat (P<0.001), and T. chebula 500 mg (P<0.01); an increase in serum uric acid levels was seen with placebo (P<0.05). The serum uric acid levels became steady after 16 weeks of treatment and remained the same until the end of 24 weeks. The reduction of serum uric acid levels in the T. bellerica 500 mg group was nearly twice that of the T. chebula 500 mg group as well as T. bellerica 250 mg group at all time points. T. bellerica 500 mg reduced serum uric acid levels from 8.07±0.87 to 5.78±0.25 compared to febuxostat, which reduced serum uric acid levels from 8.53±0.97 to 4.28±0.67 (P<0.001) at the end of 24 weeks. The efficacy of T. bellerica appeared to be dose dependent. All the formulations were well tolerated. CONCLUSION: T. bellerica has the potential for treating hyperuricemia as it was devoid of any serious adverse effects in the present study. Further studies are needed to confirm this potential.

Climate Change and the Emergent Epidemic of CKD from Heat Stress in Rural Communities: The Case for Heat Stress Nephropathy.

Climate change has led to significant rise of 0.8°C-0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves (extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions.