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Chronic kidney disease of unknown etiology (CKDu)



Last author update: 15 March 2024
Last staff update: 15 March 2024

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PubMed Search: Chronic kidney disease of unknown etiology

Michael Carstens, M.D., Ph.D.
Alexei Mikhailov, M.D., Ph.D.
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Cite this page: Carstens M, Mikhailov A. Chronic kidney disease of unknown etiology (CKDu). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneynontumorCKDu.html. Accessed April 14th, 2024.
Definition / general
  • Chronic kidney disease of unknown etiology (CKDu) is likely a multifactorial chronic kidney disease seen among manual laborers (mostly agricultural workers) in low altitude areas of tropical countries; CKDu displays features of acute and chronic tubulointerstitial nephritis
Essential features
  • Early CKDu presents as acute tubulointerstitial nephritis with almost exclusively lymphocytic infiltration
  • Many kidney damaging factors are thought to be responsible for CKDu initiation and progression; the environmental, toxicological, clinical and histological data does not support any single factor as the primary cause
  • Disease progression is generally slow and inexorable, resulting in kidney failure
  • CKDu at chronic kidney disease stages 2, 3 and 4 presents histopathologically as focal or diffuse interstitial fibrosis and tubular atrophy (IFTA) with or without lymphocytic inflammation
Terminology
  • Depending on the geographic location, CKDu is also called Mesoamerican endemic nephropathy (MeN), Sri Lankan nephropathy, Indian or Uddanam nephropathy
  • Other CKDu synonyms: chronic interstitial nephritis of unknown etiology, chronic interstitial nephritis in agricultural communities (CINAC), global warming nephropathy
  • Chronic kidney disease is defined based on the presence of kidney damage or glomerular filtration rate (GFR) < 60 mL/min per 1.73 m2 for ≥ 3 months, irrespective of the cause (Kidney Int 2011;80:1000)
ICD coding
  • ICD-10
    • N18.9 - chronic kidney disease, unspecified
    • N14.1 - nephropathy induced by other drugs, medicaments and biological substances
    • N10-N16 - renal tubulointerstitial diseases
Epidemiology
  • Tropical countries, low lying areas with hot tropical climate
  • More common in men, 20 - 60 years of age, performing hard manual labor in agriculture; also (but much less frequently), CKDu is seen among their family members and the city population
  • Incidence and prevalence rates for CKDu vary by location but are generally very high; for example, prevalence of CKDu (defined by glomerular filtration rate < 60 mL/min/1.73 m2) in a community in Nicaragua was 9.8% among women and 41.9% among men (MEDICC Rev 2014;16:16)
  • CKDu has been reported in the following geographic locations
Sites
  • Kidney
    • Tubulointerstitial compartment
    • Glomeruli
    • Blood vessels (unclear)
Pathophysiology
  • Acute kidney injury may lead to chronic kidney disease; this is the key pathogenetic event in CKDu development (N Engl J Med 2014;371:58)
  • Progressive renal fibrosis requires repetitive damage of previously normal nephrons unless primary interstitial disease is itself the instigating factor for fibrosis (J Am Soc Nephrol 2015;26:1765)
  • Progressive tubular atrophy and fibrosis are associated with failed differentiation of regenerating tubular epithelium, failure of capillary endothelial cells to regenerate and loss of vascular endothelial growth factor (VEGF) expression in proximal tubules (J Am Soc Nephrol 2015;26:1765)
  • Further research is needed to understand the mechanism of acute kidney injury in CKDu endemic regions and its progression to CKDu
Etiology
Clinical features
  • Typical presentation of CKDu is a young male from an agricultural community in an endemic area with a family history of chronic kidney disease
  • Acute kidney injury may be the first manifestation of CKDu; 8.4% of patients with acute kidney injury progress to chronic kidney disease (Kidney Int 2018;94:1205)
  • In the acute kidney injury stage of CKDu, symptoms may include low grade fever, nausea, back pain, vomiting, headache, muscle weakness and paresthesias (Am J Trop Med Hyg 2017;97:1247)
  • Anemia and paresthesias at presentation are the strongest predictors of progression to chronic kidney disease, while leukocytosis is associated with renal recovery (Kidney Int 2018;94:1205)
  • Most patients are asymptomatic during the early stages of chronic kidney disease transition
  • Nocturia, dysuria and foamy urine appear in chronic kidney disease stage 2
  • Patients are normotensive; hypertension sets in with kidney failure
Diagnosis
  • Suspected CKDu
    • Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or albuminuria > 30 mg/g creatinine or proteinuria > 150 mg/g creatinine
    • All or any of the above in the absence of hypertension, diabetes mellitus or acute kidney injury
    • Patients living and working in an agricultural community in a CKDu endemic area (Int J Nephrol Renovasc Dis 2020:13:261)
  • Probable CKDu: meets the criteria of suspected CKDu + hypokalemia or hyperuricemia in the absence of autoimmune etiology, glomerular disease, congenital kidney disease, obstructive kidney disease (Int J Nephrol Renovasc Dis 2020:13:261)
  • Confirmed CKDu: meets the criteria for probable CKDu + histopathological features consistent with CKDu on kidney biopsy in the absence of pyelonephritis and interstitial nephritis due to specific etiology (Int J Nephrol Renovasc Dis 2020:13:261)
Laboratory
  • In acute CKDu (acute kidney injury leading to CKDu), most patients display leukocytosis, neutrophilia, lymphopenia, elevated serum creatinine levels, hyperuricemia, hypokalemia, hypomagnesemia, leukocyturia, epithelial cells in urine and low level proteinuria (Am J Trop Med Hyg 2017;97:1247)
  • Nocturia, dysuria, urinary hesitancy and foamy urine appear in chronic kidney disease stage 2 and tend to progress (Nephrol Dial Transplant 2017;32:234)
  • Persistently increased excretion of magnesium, phosphate, sodium, potassium, uric acid and calcium as well as acid base disorders begin to appear in chronic kidney disease stage 2 (Nephrol Dial Transplant 2017;32:234)
Radiology description
Prognostic factors
  • CKDu is a primary chronic kidney disease with inexorable progression to kidney failure
  • CKDu patients show a mean GFR decline of -1.7 mL/min/1.73 m2 per year, with 15% of patients having a rapid progression, 35% of patients with GFR decline between -5 and -1 mL/min/1.73 m2 per year and 50% of patients with stable or improved GFR (Kidney Med 2021;3:871)
  • Risk factors: extreme poverty, agricultural fieldwork, poor hydration, lack of rest breaks, lack of workplace regulation (N Engl J Med 2014;371:58)
Case reports
  • 32 year old Salvadorian male immigrant presented with shortness of breath and leg swelling, small kidneys found on ultrasound (Am J Emerg Med 2016;34:1323.e5)
  • 39 year old male immigrant from Nicaragua presented with elevated serum creatinine, elevated uric acid levels, low potassium and magnesium levels, undergoes kidney biopsy (Cureus 2022;14:e24566)
  • 50 year old Sri Lankan man presented with loin pain, arthralgia and high serum creatinine (Kidney Int Rep 2022;7:S2)
Treatment
  • Preventive measures, such as hydration with safe water and electrolytes and providing rest and tents for shade (J Occup Environ Med 2019;61:239)
  • Restriction from performing heavy manual labor in hot weather
  • There is no etiological treatment; treatment is supportive
  • If the renal disease has progressed to end stage, dialysis or kidney transplantation are indicated
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Alexei Mikhailov, M.D., Ph.D.
IFTA with lymphocytic inflammation

IFTA with lymphocytic inflammation

Glomerulus in CKDu

Glomerulus in CKDu

Ischemic glomerulus in CKDu

Ischemic glomerulus in CKDu

Glomerular obsolescence in MEN

Glomerular obsolescence in MeN

MEN interstitial inflammatory infiltrate

MeN interstitial inflammatory infiltrate

Perihilar FSGS in CKDu

Perihilar FSGS in CKDu

Immunofluorescence description
Positive stains
  • CD3 and CD68 immunohistochemical stains highlight numerous T lymphocytes in the interstitial infiltrates and monocytes / macrophages mostly concentrated at the corticomedullary junction (Am J Trop Med Hyg 2017;97:1247)
  • CD20 and CD138 immunohistochemical stains reveal rare B cells and plasma cells in the infiltrates (Kidney Int 2018;93:681)
Electron microscopy description
  • There are no ultrastructural diagnostic findings specific for CKDu
  • Most often seen glomerular abnormalities include podocyte vacuolization and fat droplets (Am J Kidney Dis 2013;62:908, PLoS One 2018;13:e0193056)
  • Deflated capillaries with wrinkled and focally thickened glomerular basement membrane are seen in ischemic glomerular segments (Kidney Int 2018;93:681)
  • Ultrastructural examination of 34 biopsies from 3 continents demonstrated enlarged dysmorphic lysosomes in the proximal tubules, resembling the dysmorphic lysosomes seen in kidney transplant patients undergoing immunosuppressive therapy with calcineurin inhibitors (Kidney Int 2020;97:350)
Electron microscopy images

Contributed by Alexei Mikhailov, M.D., Ph.D.
MEN glomerular capillary

MeN glomerular capillary

MEN podocyte effacement

MeN podocyte effacement

Genetics
  • CKDu shows familial clustering, suggesting genetic predisposition; the disease is seen in sharply demarcated geographical regions (Clin Kidney J 2018;11:491)
  • Variants of CYP1A1 gene (cytochrome C) are associated with 1.4 - 2 fold increased risk of CKDu in Indian patients (Environ Toxicol Pharmacol 2013;36:164)
  • Polymorphisms in SLC13A3 (sodium dicarboxylate transporter 3 in the basolateral membranes of the proximal tubules) and KCNA10 (voltage gated potassium channel in glomerular endothelium and apical plasma membrane of proximal tubular epithelium) are associated with a higher risk of CKDu in Sri Lanka (J Occup Health 2014;56:28, Environ Health Prev Med 2015;20:354)
Sample pathology report
  • Kidney, biopsy:
    • 60% global glomerulosclerosis (12/20) (see comment)
    • No significant arteriosclerosis
    • Focal moderate interstitial fibrosis and tubular atrophy
    • No evidence of immune complex or monoclonal etiology
    • Comment: Significant chronic tubulointerstitial changes in a young patient working in the sugarcane industry in a CKDu endemic area, with no evidence of known etiologies or comorbidities, strongly suggests chronic kidney disease of unknown etiology (CKDu).
    • Clinical history: The patient is a 25 year old man employed as a sugarcane cutter and living in the Chinandega Department of Nicaragua. His father had chronic kidney disease. He presented to the emergency department of the Chinandega Hospital with nausea, vomiting, weakness and headaches that were gradually getting worse over several months. Laboratory data: serum creatinine 2.5 mg/dL, proteinuria 800 mg/g creatinine, urinalysis with mild proteinuria and large numbers of epithelial cells. Renal ultrasound revealed kidney pole to pole length of 97 mm and the Doppler study showed resistance index > 0.7.
    • Light microscopy: The biopsy material consists of tissue from the renal cortex and medulla. The tissue is sampled at 4 levels of section with H&E, PAS, trichrome and PAMS stains. Per level of section up to 20 glomeruli are available, of which 12 are globally sclerosed. Globally sclerosed glomeruli are often obsolescent and are mostly located in the areas of chronic tubulointerstitial changes close to the corticomedullary junction. The nonsclerosed glomeruli display patent capillary lumens, single contoured capillary walls and no segments of sclerosis, adhesion or crescents. Some glomeruli show capillary tuft deflation and wrinkled capillary walls. There are large foci of interstitial fibrosis and tubular atrophy of the usual and thyroid type with associated moderate mononuclear infiltration; nonseverely atrophic tubules show rare mild tubulitis. Tubules in the nonatrophic areas display mildly flattened epithelium with focally absent brush borders. Interlobular arteries of medium caliber are present and do not show diagnostic arteriosclerotic changes; there is no significant arteriolar hyalinosis.
    • Immunofluorescence microscopy: 6 glomeruli, 2 of them globally sclerosed, are available for evaluation by immunofluorescence microscopy. Mild granular immunofluorescence staining is present in the mesangial areas with antibodies to IgM. No diagnostic immunofluorescence staining is detected with antibodies to IgG, IgA, C3, C1q, kappa light chains and lambda light chains.
    • Electron microscopy
      • 2 glomeruli, 2 of them globally sclerosed, are available for evaluation on the semithin sections. The nonsclerosed glomeruli appear unremarkable. There is mild interstitial fibrosis and tubular atrophy and mild arteriolar hyalinosis.
      • Ultrastructural examination of 2 glomeruli show glomerular basement membranes (GBMs) of normal thickness, except in a few deflated capillary segments where the GBMs are wrinkled and somewhat thickened. Podocytes display vacuolated cytoplasm with a few lipid vacuoles. There is segmental mild podocyte foot process effacement with foci of podocyte microvillous transformation. Capillary lumens are patent. The mesangial matrix does not demonstrate expansion or hypercellularity.
Differential diagnosis
Board review style question #1

A 25 year old male agricultural worker living in California Central Valley gets an infected skin wound. He receives a course of vancomycin. Routine laboratory testing a week later revealed serum creatinine 2.2 mg/dL, proteinuria 350 mg/g creatinine and urinalysis displayed red blood cells 10 - 20/high power field, white blood cells 2/high power field. A kidney biopsy is performed and a representative H&E stained section of the main histological finding is shown above. What is the most likely diagnosis?

  1. Acute pyelonephritis
  2. Allergic tubulointerstitial nephritis
  3. Chronic kidney disease of unknown etiology (CKDu)
  4. Postinfectious glomerulonephritis
Board review style answer #1
B. Allergic tubulointerstitial nephritis. Vancomycin nephrotoxicity manifested by acute tubulointerstitial nephritis and acute kidney injury is well known (Front Med (Lausanne) 2022:9:899886). The image shows features suggestive of allergic interstitial nephritis and focal acute tubular injury, predominantly lymphocytic interstitial infiltration with many admixed eosinophils, interstitial edema, tubulitis and focal epithelial flattening and loss of brush border. Answer C is incorrect because although CKDu is in the differential diagnosis due to the demographic data, numerous eosinophils and tubulitis are not a feature of CKDu. Answer D is incorrect because postinfectious glomerulonephritis is mainly a glomerular disease clinically presenting with significant hematuria and kidney failure. Answer A is incorrect because acute pyelonephritis shows significant pyuria and polymorphonuclear neutrophil (PMN) rich interstitial inflammation with PMNs in the tubular lumens, in the tubular epithelium and the surrounding interstitium.

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Reference: Chronic kidney disease of unknown etiology (CKDu)
Board review style question #2
You are a pathologist in an international team studying an epidemic of chronic kidney disease in a tropical country. In most patients, the laboratory data shows progressive decline in kidney function and in some patients, glycosuria, hyperphosphatemia and hematuria. Encephalopathy and high blood pressure are common. Kidney biopsies show large foci of interstitial fibrosis and tubular atrophy with lymphocytic infiltration that is also sometimes seen in nonatrophic areas. Electron microscopy shows unremarkable glomeruli but the tubules contain strange enlarged mitochondria and the tubular epithelial nuclei have large inclusion bodies. The team anxiously awaits your opinion. What will you say?

  1. Lead level in the patient's blood should be urgently tested
  2. The disease is due to ingestion of indigenous herbs containing aristolochic acid
  3. This is an unknown disease and needs further investigation
  4. This is likely CKDu
Board review style answer #2
A. Lead level in the patient's blood should be urgently tested. Encephalopathy, tubular dysfunction, high blood pressure, chronic tubulointerstitial nephritis, enlarged mitochondria and inclusion bodies in the tubular epithelium are characteristic for lead toxicity. Answers B and D are incorrect because the features listed above (except for chronic tubulointerstitial nephritis) are not consistent with these etiologies.

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Reference: Chronic kidney disease of unknown etiology (CKDu)
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