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American Journal of Kidney Diseases

CKD and Infectious Diseases in Asia Pacific: Challenges and Opportunities

  • Vivekanand Jha
    Correspondence
    Address correspondence to Vivekanand Jha, MD, DM, FRCP, George Institute for Global Health, 219-221 Splendor Forum, Jasola District Center, New Delhi 110 025, India.
    Affiliations
    Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Department of Nephrology, George Institute for Global Health, New Delhi, India

    Department of Nephrology, University of Oxford, Oxford, United Kingdom
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  • Narayan Prasad
    Affiliations
    Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Published:March 02, 2016DOI:https://doi.org/10.1053/j.ajkd.2016.01.017
      The exact number of patients with chronic kidney disease (CKD) in Asia Pacific is uncertain. In numeric terms, the region is home to the largest population of patients with untreated chronic kidney failure. The climatic, geographic, social, cultural, economic, and environmental diversity within this region is higher than in any other part of the world. Large parts of the region face a climate-related burden of infectious diseases. Infections contribute to the development and progression of CKD and complicate the course of patients with pre-existing CKD (especially those on dialysis therapy or who are immunosuppressed), increase the cost of CKD care, and contribute to mortality and morbidity. Kidney involvement is a feature of several infectious diseases prevalent in Asia Pacific. Examples include malaria, leptospirosis, scrub typhus, tuberculosis, hepatitis B and C virus, dengue hemorrhagic fever, and Hantaan virus infections. The contribution of infection-associated acute kidney injury to the overall burden of CKD has not been evaluated systematically. Research is needed to quantify the impact of infections on kidney health by undertaking prospective studies. Nephrologists need to work with infectious disease research groups and government infection surveillance and control programs.

      Index Words

      Asia Pacific is a region of the world in or near the Western Pacific Ocean (Fig 1). It includes around 60% of the world’s population, which is growing,

      United Nations Economic and Social Commission for Asia and the Pacific. Statistical Yearbook for Asia and the Pacific 2014. http://www.unescap.org/resources/statistical-yearbook-asia-and-pacific-2014. Accessed October 31, 2015.

      and has the largest population density in the world. The social, cultural, economic, environmental, and religious diversity within this region is the highest in the world. Particularly striking is the disparity in economic development; only 7 countries (Japan, South Korea, Singapore, Taiwan, Brunei, Australia, and New Zealand) in Asia Pacific are classified as developed countries. The others are in various stages of development and are considered “emerging economies.” Most have agrarian economies, with a large number of people living in remote rural locations. Poorly managed economies, lack of skilled human resources and technology, weak infrastructure, and an inappropriate health policy framework obstruct improvements to health care delivery, as exemplified by failure to reach the health-related Millennium Development Goals.

      MDG Gap Task Force. The State of the Global Partnership for Development MDG Gap Task Force Report 2014. New York, NY: United Nations; 2014. apps.who.int/medicinedocs/documents/s21775en/s21775en.pdf. Accessed July 12, 2015.

      Figure thumbnail gr1
      Figure 1Countries and territories typically included in the definition of Asia Pacific. Light green indicates those included in only a few definitions (Siberia is also sometimes included).
      Reproduced from Wikimedia Commons (https://en.wikipedia.org/wiki/File:Asia-Pacific.png; version 19:07, 28 December 2014).
      The disease spectrum in most parts of America and Europe has changed from infections to noncommunicable diseases. This contrasts with large parts of Asia Pacific, which faces a climate-related burden of infectious diseases. Poverty increases the likelihood of exposure to infection-related health risks. The 2010 Global Burden of Disease Study
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      reported that infections are responsible for 40% to 60% of deaths and disability-adjusted life-years in the low-income parts of Asia Pacific. Many of these infections are complicated by kidney injury. However, the Global Burden of Disease Study data do not allow an estimation of the contributions of kidney involvement to death and disability-adjusted life-years. However, several individual studies have shown that kidney involvement is an independent and major contributor to mortality and morbidity in these infections.
      • Basu G.
      • Chrispal A.
      • Boorugu H.
      • et al.
      Acute kidney injury in tropical acute febrile illness in a tertiary care centre–RIFLE criteria validation.
      • Kumar S.
      • Ramachandran R.
      • Mete U.
      • et al.
      Acute pyelonephritis in diabetes mellitus: single center experience.
      • Kumar V.
      • Yadav A.K.
      • Iyengar S.
      • et al.
      Scrub typhus is an under-recognized cause of acute febrile illness with acute kidney injury in India.
      • Jha V.
      • Chugh K.S.
      Malaria and acute kidney injury.
      According to data collected by the International Society of Nephrology as part of its 0by25 initiative,
      • Mehta R.L.
      • Cerda J.
      • Burdmann E.A.
      • et al.
      International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.
      the mortality rate of infection associated with acute kidney injury (AKI) in Asia was ∼52%. Importantly, 7% to 16% of patients went on to develop chronic kidney failure, and 11% to 19% were left with decreased kidney function despite being cured of the infection.
      • Mehta R.L.
      • Cerda J.
      • Burdmann E.A.
      • et al.
      International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.
      Another recent study showed faster declines in glomerular filtration rates in patients who showed high titers of anti-leptospira antibodies, indicating past exposure to this organism.
      • Yang H.Y.
      • Hung C.C.
      • Liu S.H.
      • et al.
      Overlooked risk for chronic kidney disease after leptospiral infection: a population-based survey and epidemiological cohort evidence.
      Asia Pacific also exhibits an enormous variation of climate and topography, from tropical to arctic and from the Himalayas to coral reefs. Most countries fall either completely or partially in the tropical zone. The tropical climate is characterized by high ambient temperatures and humidity and is conducive to growth of various life forms, making it a large reservoir for vectors responsible for disease transmission. Some of these climate-sensitive conditions include diarrheal diseases and vector-borne infections, major preventable causes of kidney diseases.

      Sachs JM. Why tropical countries are underdeveloped. The National Bureau of Economic Research Working Paper Series [online]. http://www.nber.org/papers/w8119.html (2001). Accessed October 31, 2015.

      The relationship with infection and chronic kidney disease (CKD) is bidirectional. Infections contribute to the development and progression of CKD but do not receive adequate recognition and complicate the course of patients with pre-existing CKD. They are more severe, detected late, and harder to manage; increase the cost of CKD care; and contribute to mortality and morbidity.
      • Dalrymple L.S.
      • Go A.S.
      Epidemiology of acute infections among patients with chronic kidney disease.
      • Jha V.
      • Chugh S.
      • Chugh K.S.
      Infections in dialysis and transplant patients in tropical countries.
      • Jha V.
      • Garcia-Garcia G.
      • Iseki K.
      • et al.
      Chronic kidney disease: global dimension and perspectives.
      We describe the burden of CKD in Asia Pacific with the possible links to infection and the impact of infections on patients with pre-existing CKD.

      Overview of CKD in Asia Pacific

      Epidemiology

      In Asia Pacific, the incidence and prevalence of chronic kidney failure and the resulting need for renal replacement therapies (RRTs) are increasing rapidly. Except for Japan, Taiwan, South Korea, Australia, and New Zealand, where RRT is widely available, access to this life-saving but expensive therapy is limited in other countries in the region. According to a recent report,
      • Liyanage T.
      • Ninomiya T.
      • Jha V.
      • et al.
      Worldwide access to treatment for end-stage kidney disease: a systematic review.
      of about 2.89 million people who needed RRT in Asia and Oceania in 2010, only 0.993 million received the therapy. This number is likely to grow in coming years, making it imperative to develop CKD detection and prevention programs.
      The incidence and prevalence of earlier stages of CKD are uncertain, primarily because of the lack of large-scale epidemiologic studies. Published studies show figures ranging from 9% to 17%.

      Yang CW. Prevalence of CKD in Asia. Seoul, Korea: Asian Pacific Congress of Nephrology; 2010. http://isn-india.org/UserFiles/Image/images/images/Yang%20APCN%202010.pdf. Accessed October 31, 2015.

      The variations are explained by the different definitions of CKD. Studies that included hematuria (which might be a surrogate for infection-related proliferative glomerulonephritis [GN]) to define CKD generally show a higher CKD prevalence.
      • Iseki K.
      Nephrology for the people: Presidential Address at the 42nd Regional Meeting of the Japanese Society of Nephrology in Okinawa 2012.
      • Zhang L.
      • Wang F.
      • Wang L.
      • et al.
      Prevalence of chronic kidney disease in China: a cross-sectional survey.
      • Zhang L.
      • Zhang P.
      • Wang F.
      • et al.
      Prevalence and factors associated with CKD: a population study from Beijing.

      Etiology

      The etiologic spectrum of CKD is also not uniform in countries within the region. Despite the incessant increase in proportion of patients with CKD caused by diabetes, chronic GN and chronic interstitial nephritis remain the leading causes of CKD in several countries. Chronic GN remains dominant in China, Indonesia, and Malaysia,
      • Liu W.J.
      • Hooi L.S.
      Patients with end stage renal disease: a registry at Sultanah Aminah Hospital, Johor Bahru, Malaysia.
      • Prodjosudjadi W.
      Incidence, prevalence, treatment and cost of end-stage renal disease in Indonesia.
      • Wang H.
      • Zhang L.
      • Lv J.
      Prevention of the progression of chronic kidney disease: practice in China.
      whereas a high frequency of chronic interstitial nephritis has been described from parts of South Asia.
      • Gooneratne I.K.
      • Ranaweera A.K.
      • Liyanarachchi N.P.
      • Gunawardane N.
      • Lanerolle R.D.
      Epidemiology of chronic kidney disease in a Sri Lankan population.
      • Mani M.K.
      Chronic renal failure in India.
      • Rajapurkar 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.
      Infections play an important etiologic role in both these conditions. Some parts of the region report a high prevalence of CKD of unknown cause.
      • Gooneratne I.K.
      • Ranaweera A.K.
      • Liyanarachchi N.P.
      • Gunawardane N.
      • Lanerolle R.D.
      Epidemiology of chronic kidney disease in a Sri Lankan population.
      • Rajapurkar 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.
      • Jayasekara K.B.
      • Dissanayake D.M.
      • Sivakanesan R.
      • Ranasinghe A.
      • Karunarathna R.H.
      • Priyantha Kumara G.W.
      Epidemiology of chronic kidney disease, with special emphasis on chronic kidney disease of uncertain etiology, in the north central region of Sri Lanka.
      The role of locally prevalent infections also needs consideration in light of the poor sanitation, unsafe water, overcrowding, and widespread presence of disease-transmitting vectors in the region.
      Several infectious diseases prevalent in Asia Pacific, such as malaria, leptospirosis, tuberculosis (TB), human immunodeficiency virus (HIV)/AIDS, dengue hemorrhagic fever, and Hantaan virus infections, affect the kidneys (Box 1). The primary presentation is in the form of AKI, either de novo or on the background of CKD. Of patients who recover from AKI, as many as 28% of those who had no history of kidney disease progress to CKD.
      • Mehta R.L.
      • Cerda J.
      • Burdmann E.A.
      • et al.
      International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.
      • Bucaloiu I.D.
      • Kirchner H.L.
      • Norfolk E.R.
      • Hartle 2nd, J.E.
      • Perkins R.M.
      Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury.
      • Wu V.C.
      • Shiao C.C.
      • Chang C.H.
      • et al.
      Long-term outcomes after dialysis-requiring acute kidney injury.
      • Taylor A.J.
      • Paris D.H.
      • Newton P.N.
      A systematic review of the mortality from untreated leptospirosis.
      • Susantitaphong P.
      • Cruz D.N.
      • Cerda J.
      • et al.
      World incidence of AKI: a meta-analysis.
      In those with pre-existing CKD, infections often accelerate the rate of progression.
      • Dalrymple L.S.
      • Go A.S.
      Epidemiology of acute infections among patients with chronic kidney disease.
      Many of these patients have multiple comorbid conditions, making it difficult to dissect the role of kidney involvement on the overall outcome.
      Infections in Asia Pacific That Affect the Kidneys
      Viral infections
      • Hepatitis B virus
      • Hepatitis C virus
      • Human immunodeficiency virus (HIV)
      • Hantaan viruses
      • Dengue virus
      Parasitic infections
      • Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi
      • Wuchereria bancrofti
      • Brugia malayi, Brugia timori
      • Leishmania donovani (kala-azar)
      Bacterial infections
      • Leptospira interrogans
      • Orientia tsutsugamushi (scrub typhus )
      • Mycobacterium tuberculosis
      • Mycobacterium leprae
      • Streptococci and staphylococci
        • Infection-associated glomerulonephritis
        • Infection-associated interstitial nephritis
        • Visceral and puerperal sepsis
      • Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and other bacteria (often multidrug resistant)
      • Urinary tract infection
      Fungal infections
      • Candida
      • Aspergillus
      • Zygomycetes
      Kidney injury in infections prevalent in Asia Pacific may occur as a result of several mechanisms. These include direct invasion by the offending microorganism leading to cytopathic injury, as in pyogenic infections, TB, leptospirosis, and nematode infestations; through immune mechanisms involving microbial antigens that might lead to the generation of circulating or in situ immune complexes or cause perturbations in innate and cellular immunity, as in infection-related GN; and by systemic inflammatory response syndrome, hemodynamic disturbance, multiorgan failure, hemolysis, rhabdomyolysis, hepatorenal syndrome, and nephrotoxicity of antimicrobial therapy.
      The following section describes specific infections that lead to kidney disease in Asia Pacific.

      Infection-related Causes of Kidney Disease in Asia Pacific

      Viral Infections

      Hepatitis B Virus

      About 75% of the 350 million people affected with hepatitis B virus (HBV) worldwide are from Asia.
      • Merican I.
      • Guan R.
      • Amarapuka D.
      • et al.
      Chronic hepatitis B virus infection in Asian countries.
      • Tandon B.N.
      • Acharya S.K.
      • Tandon A.
      Epidemiology of hepatitis B virus infection in India.
      The reported prevalence of kidney disease related to HBV infection closely aligns with the geographic distribution of HBV prevalence in the region, which ranges from 2.8% in South Korea to 20% in Taiwan and Vietnam.
      • Chan T.M.
      Hepatitis B and renal disease.
      • Kusakabe A.
      • Tanaka Y.
      • Kurbanov F.
      • et al.
      Virological features of hepatitis B virus-associated nephropathy in Japan.
      • Mohamed R.
      • Desmond P.
      • Suh D.J.
      • et al.
      Practical difficulties in the management of hepatitis B in the Asia-Pacific region.
      In a retrospective analysis of 11,618 kidney biopsies performed from 1987 to 2012 at a single center in Beijing, China, 3% were reported to have HBV-associated nephritis.
      • Zhang X.
      • Liu S.
      • Tang L.
      • et al.
      Analysis of pathological data of renal biopsy at one single center in China from 1987 to 2012.
      Of the 3 primary forms of GN linked with HBV infection (membranous GN, membranoproliferative GN, and immunoglobulin A [IgA] nephropathy), membranous GN is most commonly reported in Asian populations, particularly among children.
      • Takekoshi Y.
      • Tochimaru H.
      • Nagata Y.
      • Itami N.
      Immunopathogenetic mechanisms of hepatitis B virus-related glomerulopathy.
      • Zeng C.H.
      • Chen H.M.
      • Wang R.S.
      • et al.
      Etiology and clinical characteristics of membranous nephropathy in Chinese patients.
      In some areas, HBV-related disease accounts for up to 15% of all membranous nephropathy cases.
      • Gupta A.
      • Quigg R.J.
      Glomerular diseases associated with hepatitis B and C.
      By comparison, mesangial proliferative forms with IgA deposits appear to be more common in adults. An association of HBV infection has also been described with mixed cryoglobulinemia, polyarteritis nodosa, and focal segmental glomerulosclerosis.
      • Khaira A.
      • Upadhyay B.K.
      • Sharma A.
      • et al.
      Hepatitis B virus associated focal and segmental glomerular sclerosis: report of two cases and review of literature.
      The introduction of nationwide HBV vaccination in China in 1992 led to significant decreases in childhood glomerular disease.
      • Sun L.
      • Xu H.
      • Zhou L.J.
      • Fang L.J.
      • Guo Y.Q.
      [Effect of hepatitis B vaccine immunization on HBV associated nephritis in children].

      Hepatitis C Virus

      Asia Pacific is home to 100 million of about 170 million individuals worldwide infected with hepatitis C virus (HCV).
      • McCaughan G.W.
      • Omata M.
      • Amarapurkar D.
      • et al.
      Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection.
      The majority are in the Western Pacific (62.2 million) and Southeast Asia (32.3 million). The prevalence of antibodies to HCV is estimated to range from 0.3% to 5.6% in New Zealand and Thailand, respectively. HCV hyperendemic parts of Japan, Vietnam, and Taiwan have prevalence rates of 12% to 58%.
      • Yu M.L.
      • Chuang W.L.
      Treatment of chronic hepatitis C in Asia: when East meets West.
      In contrast to HBV infection, HCV infection is marked by a silent onset and chronic course. The virus’ behavior and response to treatment vary according to its genotype and host characteristics. Genotype 1, the most virulent form, is the most frequent form encountered in Australia and North Asia; genotype 6, in Southeast Asia; and the less virulent genotype 3, in India and Pakistan.
      • Gupta V.
      • Kumar A.
      • Sharma P.
      • et al.
      Sustained virological response rates to antiviral therapy in genotype 1 and 3 chronic hepatitis C patients: a study from north India.
      • Sievert W.
      • Altraif I.
      • Razavi H.A.
      • et al.
      A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt.
      There is a robust and probably causal association between chronic HCV infection and several chronic glomerular diseases.
      • Perico N.
      • Cattaneo D.
      • Bikbov B.
      • Remuzzi G.
      Hepatitis C infection and chronic renal diseases.
      • Uchiyama-Tanaka Y.
      • Mori Y.
      • Kishimoto N.
      • et al.
      Membranous glomerulonephritis associated with hepatitis C virus infection: case report and literature review.
      An autopsy study revealed glomerular lesions in 55% of HCV-infected individuals, including mesangial proliferative GN (17.6%), membranoproliferative GN (11.2%), and membranous nephropathy (2.7%).
      • Arase Y.
      • Ikeda K.
      • Murashima N.
      • et al.
      Glomerulonephritis in autopsy cases with hepatitis C virus infection.
      Recent population-based studies have shown a link between HCV infection and proteinuria.
      • Fabrizi F.
      • Verdesca S.
      • Messa P.
      • Martin P.
      Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis.
      Kidney disease is often clinically silent, and the presence of infection is detected only during workup. Management of these patients is particularly difficult when detected late. The recent discovery of orally active antiviral agents has the potential to revolutionize the treatment of HCV-related kidney diseases. However, the high cost of treatment is likely to delay the introduction of these agents.
      • Lim S.G.
      • Dan Y.Y.
      A 2015 roadmap for the management of hepatitis C virus infections in Asia.

      HIV Infection

      The Joint United Nations Programme on HIV/AIDS (UNAIDS) 2013 report estimated that there were about 350,000 new cases of HIV infection in Asia Pacific in 2012, which represents a decline of ∼26% since 2001.
      Joint United Nations Programme on HIV/AIDS (UNAIDS)
      HIV in Asia and the Pacific.
      The increased risk for both AKI and CKD in HIV-infected patients is well known. However, in contrast to the black population from sub-Saharan Africa, Asians infected with HIV seem to be at a lower risk for developing HIV-associated nephropathy. In most series of patients with HIV infection and kidney disease from the region, kidney disease seems to have been etiologically unrelated to the HIV infection.
      • Agarwal D.K.
      • Hota J.K.
      • Nag N.
      • Mehta S.N.
      Renal transplantation in HIV patients: a series of four cases.
      • Praditpornsilpa K.
      • Napathorn S.
      • Yenrudi S.
      • Wankrairot P.
      • Tungsaga K.
      • Sitprija V.
      Renal pathology and HIV infection in Thailand.
      • Pujari S.N.
      • Smith C.
      • Makane A.
      • et al.
      Higher risk of renal impairment associated with tenofovir use amongst people living with HIV in India: a comparative cohort analysis between Western India and United Kingdom.
      At the same time, these patients remain at increased risk for kidney disease as a result of predilection to other infections or drug nephrotoxicity.
      • Pujari S.N.
      • Smith C.
      • Makane A.
      • et al.
      Higher risk of renal impairment associated with tenofovir use amongst people living with HIV in India: a comparative cohort analysis between Western India and United Kingdom.

      Dengue Virus

      Dengue, transmitted by the bite of the Aedes aegypti mosquito, is endemic in several Asia Pacific countries. More than 70% of the 2.5 million people affected globally live in the region, 35% in Southeast Asia alone.

      WHO Regional Office for South-East Asia. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. 2011. http://www.searo.who.int/entity/vector_borne_tropical_diseases/documents/SEAROTPS60/en/. Accessed July 12, 2015.

      The nature of kidney involvement ranges from asymptomatic urinary abnormalities to AKI. AKI develops in about 1% to 5% of all patients but is seen in 33% of fatal cases.
      • Lee H.W.
      Hemorrhagic fever with renal syndrome in Korea.
      • Wiwanitkit V.
      Acute renal failure in the fatal cases of dengue hemorrhagic fever, a summary in Thai death cases.
      • Varma M.D.
      • Vengalil S.
      • Vallabhajosyula S.
      • Krishnakumar P.C.
      • Vidyasagar S.
      Leptospirosis and dengue fever: a predictive model for early differentiation based on clinical and biochemical parameters.
      Histology usually shows proliferative immune complex GN. The long-term outcome of patients with dengue and kidney involvement has not been studied. Some studies have reported a high prevalence of persistent proteinuria and hematuria.
      • Boonpucknavig V.
      • Bhamarapravati N.
      • Boonpucknavig S.
      • Futrakul P.
      • Tanpaichitr P.
      Glomerular changes in dengue hemorrhagic fever.
      • Futrakul P.
      • Poshyachinda V.
      • Mitrakul C.
      • et al.
      Renal involvement and reticulo-endothelial-system clearance in dengue hemorrhagic fever.

      Hantaan Viruses

      Infection with this zoonotic rodent-borne virus causes hemorrhagic fever with kidney and lung injury. Kidney disease is the dominant manifestation in Asia Pacific, presenting as AKI, proteinuria, and hematuria.
      • Ala-Houhala I.
      • Koskinen M.
      • Ahola T.
      • et al.
      Increased glomerular permeability in patients with nephropathia epidemica caused by Puumala hantavirus.
      RRT is needed in 30% to 40% of patients and is associated with high mortality.
      • Lee J.S.
      Clinical features of hemorrhagic fever with renal syndrome in Korea.
      Large numbers of deaths have been reported from China and South Korea.
      • Lee H.W.
      Hemorrhagic fever with renal syndrome in Korea.
      • Chen H.X.
      • Qiu F.X.
      • Dong B.J.
      • et al.
      Epidemiological studies on hemorrhagic fever with renal syndrome in China.
      • Zhang Y.H.
      • Ge L.
      • Liu L.
      • et al.
      The epidemic characteristics and changing trend of hemorrhagic fever with renal syndrome in Hubei Province, China.
      Of those who recover from the acute phase, a significant proportion are left with residual decreased glomerular filtration rate and may develop hypertension.
      • Kleinknecht D.
      • Rollin P.E.
      Hypertension after hemorrhagic fever with renal syndrome.
      • Miettinen M.H.
      • Makela S.M.
      • Ala-Houhala I.O.
      • et al.
      Tubular proteinuria and glomerular filtration 6 years after Puumala hantavirus-induced acute interstitial nephritis.
      • Pergam S.A.
      • Schmidt D.W.
      • Nofchissey R.A.
      • Hunt W.C.
      • Harford A.H.
      • Goade D.E.
      Potential renal sequelae in survivors of hantavirus cardiopulmonary syndrome.

      Bacterial Infections

      Bacterial infection continues to be a major health problem in many countries of Asia Pacific. Kidneys are particularly vulnerable to certain types of bacterial infections. In particular, there is the persisting high-frequency AKI in the setting of puerperal and postabortal sepsis secondary to poor obstetric care in the underdeveloped rural areas of Asia Pacific.
      • Jha V.
      • Parameswaran S.
      Community-acquired acute kidney injury in tropical countries.
      In many hospitals, about one-third of all AKI cases are following obstetric complications. Of those who survive the infection, as many as 20% develop irreversible kidney failure due to acute renal cortical necrosis, and another one-third show incomplete renal recovery.
      • Jha V.
      Tropical renal diseases.
      • Naqvi R.
      • Akhtar F.
      • Ahmed E.
      • et al.
      Acute renal failure of obstetrical origin during 1994 at one center.
      • Chugh K.S.
      • Jha V.
      • Sakhuja V.
      • Joshi K.
      Acute renal cortical necrosis–a study of 113 patients.

      Mycobacterial Infections

      TB and leprosy are the 2 common infections caused by mycobacteria. Both are endemic in South and Southeast Asia and may involve the kidneys.

      Tuberculosis

      TB is common in Southeast Asia, with an incidence of 211 per 100,000 population. Although the incidence is higher in Africa (281/100,000), Southeast Asia has the largest number of TB cases in the world (5.4 million in 2014).

      World Health Organization. Global Tuberculosis Report 2015. http://www.who.int/tb/publications/global_report/en/. Accessed February 21, 2016.

      Involvement of the genitourinary tract is seen in 6% to 8% of all cases of TB,
      • Eastwood J.B.
      • Corbishley C.M.
      • Grange J.M.
      Tuberculosis and the kidney.
      with males twice as likely as females to be affected. The infection reaches the kidneys through the bloodstream, but the involvement of the collecting system (urinary bladder and ureters) leads to obstructive nephropathy. When unrecognized, destructive caseous lesions involve the renal parenchyma, causing permanent loss manifesting as “putty kidney” (Fig 2).
      • Kumar V.
      • Jha V.
      • Sakhuja V.
      Putty kidney.
      Renal TB can also present with progressive kidney injury due to granulomatous interstitial nephritis that may be difficult to distinguish from sarcoidosis.
      • Agrawal V.
      • Kaul A.
      • Prasad N.
      • Sharma K.
      • Agarwal V.
      Etiological diagnosis of granulomatous tubulointerstitial nephritis in the tropics.
      TB is the most common cause of AA (secondary) amyloidosis in the Indian subcontinent.
      • Chugh K.S.
      • Datta B.N.
      • Singhal P.C.
      • Jain S.K.
      • Sakhuja V.
      • Dash S.C.
      Pattern of renal amyloidosis in Indian patients.
      Renal amyloid can develop several years after the diagnosis and treatment of TB. The diagnosis of TB is difficult due to unsatisfactory culture techniques and lack of the newer nucleic acid–based tests.
      • Jha V.
      • Garcia-Garcia G.
      • Iseki K.
      • et al.
      Chronic kidney disease: global dimension and perspectives.
      • Jha V.
      Current status of end-stage renal disease care in South Asia.
      Smear positivity in urine is unreliable for the diagnosis of genitourinary TB because the urinary tract can be colonized by environmental mycobacteria.
      Figure thumbnail gr2
      Figure 2Putty kidney in a patient with genitourinary tuberculosis. (Left panel) Plain abdominal radiograph shows calcified kidney (short arrow) and ureteral wall calcification (long arrows). (Right panel) Computed tomographic scan shows totally calcified left kidney (arrow) and mural calcification of left ureter.
      Reproduced from Kumar et al.
      • Kumar V.
      • Jha V.
      • Sakhuja V.
      Putty kidney.

      Leprosy

      Despite a large reduction in prevalence, this disease remains endemic in several parts of South Asia and where cases with high bacillary load still occur. In a report of 122 cases from India, reduced creatinine clearance and proteinuria were common.
      • Bajaj A.K.
      • Gupta S.C.
      • Sinha S.N.
      • Govil D.C.
      • Gaur U.C.
      Sequential renal functions in leprosy.
      Autopsy studies revealed a wide spectrum of renal lesions, including renal amyloidosis, GN, tubulointerstitial nephritis, and granulomatous disease (in decreasing order of frequency).
      • Chugh K.S.
      • Sakhuja V.
      Renal lesions in leprosy.

      Protozoal Infections

      Malaria

      More than 2.2 billion people in Asia Pacific live in malaria endemic zones, representing about two-thirds of the world’s at-risk population. These include 6 of the top 10 countries worldwide with the largest at-risk populations: India, China, Indonesia, Bangladesh, Vietnam, and the Philippines.
      Institute for Health Policy
      Burden of Malaria and other Infectious Diseases in the Asia and Pacific Region Prepared for Regional Malaria Financing Task Force.
      Of the 5 human malarial parasites—Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium malariae, and Plasmodium ovale—the first 3 are prevalent in the region and cause kidney disease.
      Kidney involvement is mostly a feature of P falciparum infection. The usual presentation is with AKI. A small but significant proportion exhibit glomerular involvement, either acute nephritic syndrome or nephrotic syndrome.
      • Jha V.
      • Chugh K.S.
      Malaria and acute kidney injury.
      The prevalence of kidney involvement varies from <1% in uncomplicated infections to >50% in severe malaria.
      • Sakjuja V.
      • Kohli H.S.
      Malaria.
      Blackwater fever, seen in the setting of glucose-6-phosphate dehydrogenase deficiency, is encountered among children infected with P falciparum malaria from Southeast Asia and parts of Northeastern India.
      • Tran T.H.
      • Day N.P.
      • Ly V.C.
      • et al.
      Blackwater fever in southern Vietnam: a prospective descriptive study of 50 cases.
      • Hue N.T.
      • Charlieu J.P.
      • Chau T.T.
      • et al.
      Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population.
      • Jamaiah I.
      • Rohela M.
      • Nissapatorn V.
      • et al.
      Malaria: a 10-year (1994-2003) retrospective study at University Malaya Medical Center (UMMC), Kuala Lumpur, Malaysia.
      Ingestion of quinine precipitates intravascular hemolysis, leading to AKI, which in turn substantially increases mortality risk. Provision of RRT to these patients presents a challenge in resource-constrained environments because modern methods such as continuous RRTs are often not available. In such situations peritoneal dialysis (PD) is often life-saving.
      • Finkelstein F.O.
      • Smoyer W.E.
      • Carter M.
      • Brusselmans A.
      • Feehally J.
      Peritoneal dialysis, acute kidney injury, and the Saving Young Lives program.
      Previously considered benign, kidney involvement in P vivax infection is now being reported from South Asia, sometimes with severe and irreversible injury, especially in children.
      • Chung B.H.
      • Lee S.W.
      • Lee S.E.
      • Hwang T.J.
      • Shin H.S.
      Predictors of Plasmodium vivax malaria-induced nephropathy in young Korean men.
      • Kaushik R.
      • Kaushik R.M.
      • Kakkar R.
      • Sharma A.
      • Chandra H.
      Plasmodium vivax malaria complicated by acute kidney injury: experience at a referral hospital in Uttarakhand, India.
      • Naqvi R.
      • Ahmad E.
      • Akhtar F.
      • Naqvi A.
      • Rizvi A.
      Outcome in severe acute renal failure associated with malaria.
      • Bhatt G.C.
      • Nandan D.
      • Dewan V.
      • Dey S.
      Plasmodium vivax presenting as acute glomerulonephritis in a 3-year-old child.
      • Nayak K.C.
      • Kumar S.
      • Gupta B.K.
      • et al.
      Clinical and histopathological profile of acute renal failure caused by falciparum and vivax monoinfection: an observational study from Bikaner, northwest zone of Rajasthan, India.
      Kidney involvement in P knowlesi infection has been described from Thailand and Malaysia, where it has become the predominant cause of malarial kidney injury.
      • Sabbatani S.
      • Fiorino S.
      • Manfredi R.
      The emerging of the fifth malaria parasite (Plasmodium knowlesi): a public health concern?.
      • William T.
      • Menon J.
      • Rajahram G.
      • et al.
      Severe Plasmodium knowlesi malaria in a tertiary care hospital, Sabah, Malaysia.
      This phenomenon likely represents a change in virulence characteristics of these 2 organisms and needs further studies.
      The pathogenesis of kidney injury in malaria is multifactorial, with the main abnormality being hemodynamic alterations produced by unique properties of this parasite, which produces hemorheologic changes leading to renal ischemia. Other factors include volume depletion, intravascular hemolysis, rhabdomyolysis, and altered levels of vasoactive cytokines.
      • Jha V.
      • Chugh K.S.
      Malaria and acute kidney injury.
      Histology usually shows acute tubular necrosis, with occasional pigment casts.

      Leishmaniasis

      This disease, also known as kala-azar, is mostly seen in rural areas of the Indian subcontinent.
      It is caused by Leishmania donovani, transmitted to humans by the bite of infected female sand flies. The organism predominantly involves the reticuloendothelial system, explaining the presentation with prolonged fever and hepatosplenomegaly. About 60% of patients exhibit proteinuria and urinary sediment abnormalities, implying the presence of proliferative GN, often associated with chronic tubulointerstitial damage.
      • De Brito T.
      • Hoshino-Shimizu S.
      • Neto V.A.
      • Duarte I.S.
      • Penna D.O.
      Glomerular involvement in human kala-azar. A light, immunofluorescent, and electron microscopic study based on kidney biopsies.
      • Dutra M.
      • Martinelli R.
      • de Carvalho E.M.
      • Rodrigues L.E.
      • Brito E.
      • Rocha H.
      Renal involvement in visceral leishmaniasis.
      Antimonials used to treat the disease can worsen proteinuria and CKD.

      Fungal Infections

      Candida, Aspergillus, and Zygomycetes species cause the main fungal infections that involve the kidney and urinary tract in Asia Pacific. The first 2 are usually ascending infections in patients on long-term antibiotic therapy and with indwelling catheters, whereas the third is an angioinvasive infection that causes devastating kidney damage. Renal zygomycosis has been described mainly from India and presents as a febrile illness with invasion of renal vessels leading to tissue infarction.
      • Jha V.
      • Chugh S.
      • Chugh K.S.
      Infections in dialysis and transplant patients in tropical countries.
      • Gupta K.L.
      • Gupta A.
      Mucormycosis and acute kidney injury.
      • Gupta K.L.
      • Joshi K.
      • Sud K.
      • et al.
      Renal zygomycosis: an under-diagnosed cause of acute renal failure.
      When bilateral (Fig 3), it causes irreversible kidney failure and carries high mortality despite antifungal therapy and tissue debridement.
      Figure thumbnail gr3
      Figure 3Contrast-enhanced computed tomographic scan shows lack of enhancement of renal parenchyma secondary to infarction due to renal zygomycosis. A thin rim of enhancement is seen in the posterior aspect of the left kidney (arrowheads).

      Other Infections

      Lymphatic Filariasis

      Caused by Culex mosquitoes transmitting the nematodes Wuchereria bancrofti, Brugia malayi, or Brugia timori, lymphatic filariasis is endemic to several countries in the region. India alone accounts for 40% of the global prevalence.
      No authors listed
      Global Programme to eliminate lymphatic filariasis: progress report on mass drug administration, 2010.
      Kidney involvement manifests as chyluria (passage of “milky” urine) and hematuria, which occur because of obstruction of the central lymphatic channels by filarial worms leading to dilatation and rupture of lacteals into the collecting system.
      • Gulati S.
      • Gupta N.
      • Singh N.P.
      • et al.
      Chyluria with proteinuria or filarial nephropathy? An enigma.
      • Kaul A.
      • Bhadhuria D.
      • Bhat S.
      • et al.
      Chyluria: a mimicker of nephrotic syndrome.
      Chylous urine tests positive for protein and may lead to a mistaken diagnosis of nephrotic syndrome.
      A variety of glomerular lesions, independent of chyluria, has also been described in association with filariasis.

      Prakash GK, Vankalakunti M, Ballal HS. Microfilaria associated macroscopic hematuria and nephrotic range proteinuria. Indian J Nephrol, in press.

      A role for bacterial coinfection has been suggested. Once established, both chyluria and GN persist despite successful treatment of filariasis. Figure 4 shows a spectrum of renal abnormalities in filariasis.
      Figure thumbnail gr4
      Figure 4Kidney disease in filariasis. (A) Milky white urine in a patient with chyluria due to filariasis. (B) Retrograde pyelogram in the same patient shows retrograde filling of lacteals (arrowheads). (C) Microfilariae in glomerular capillary lumen (arrowheads) in a patient with nephrotic syndrome (scale bar, 4 μm). The urinary abnormalities resolved following diethylcarbamazine therapy.

      Scrub Typhus

      This has been identified by the World Health Organization (WHO) as a re-emerging disease in South Asia, Southeast Asia, and the Southwestern Pacific region. Scrub typhus is caused by the spirochete Orientia tsutsugamushi, which is transmitted by an infected trombiculid mite. Scrub typhus accounts for about 23% to 50% of all acute febrile episodes in endemic regions in Asia
      • Basu G.
      • Chrispal A.
      • Boorugu H.
      • et al.
      Acute kidney injury in tropical acute febrile illness in a tertiary care centre–RIFLE criteria validation.
      and has a case fatality rate of up to 50% if untreated.
      • Kumar V.
      • Yadav A.K.
      • Iyengar S.
      • et al.
      Scrub typhus is an under-recognized cause of acute febrile illness with acute kidney injury in India.

      World Health Organization. WHO Recommended Surveillance Standards WHO/CDS/CSR/ISR/99.2. 2nd ed: http://www.who.int/csr/resources/publications/surveillance/whocdscsrisr992syn.pdf. Accessed October 31, 2015.

      Kidney involvement is seen in ∼80% of cases, with AKI in 53%.
      • Kumar V.
      • Yadav A.K.
      • Iyengar S.
      • et al.
      Scrub typhus is an under-recognized cause of acute febrile illness with acute kidney injury in India.
      • Varghese G.M.
      • Abraham O.C.
      • Mathai D.
      • et al.
      Scrub typhus among hospitalised patients with febrile illness in South India: magnitude and clinical predictors.
      Because this complication has come to light only recently, the long-term kidney disease outcome in these patients is unknown.

      Leptospirosis

      Leptospirosis, the most common zoonosis worldwide, is prevalent in India, Southeast Asia, and Oceania.
      • Sharma S.
      • Vijayachari P.
      • Sugunan A.P.
      • Natarajaseenivasan K.
      • Sehgal S.C.
      Seroprevalence of leptospirosis among high-risk population of Andaman Islands, India.
      • Victoriano A.F.
      • Smythe L.D.
      • Gloriani-Barzaga N.
      • et al.
      Leptospirosis in the Asia Pacific region.
      Caused by the spirochete Leptospira interrogans, the disease is transmitted when the organism present in animal urine comes in contact with abraded human skin or mucosal surfaces and gains entry to the circulation. Seroprevalence varies from 20% to 53% in endemic areas.
      • Bharti A.R.
      • Nally J.E.
      • Ricaldi J.N.
      • et al.
      Leptospirosis: a zoonotic disease of global importance.
      Disease outbreaks are encountered during flooding in low-lying areas. Presentation as classic Weil disease is with an acute febrile illness with AKI, jaundice, myositis, and tissue hemorrhages.
      • Taylor A.J.
      • Paris D.H.
      • Newton P.N.
      A systematic review of the mortality from untreated leptospirosis.
      The spectrum of kidney injury includes mild proteinuria, urinary sediment abnormalities, tubular dysfunctions, and AKI primarily due to interstitial nephritis.
      • Jha V.
      • Parameswaran S.
      Community-acquired acute kidney injury in tropical countries.
      • Daher Ede F.
      • de Abreu K.L.
      • da Silva Jr., G.B.
      Leptospirosis-associated acute kidney injury.
      • Seguro A.C.
      • Lomar A.V.
      • Rocha A.S.
      Acute renal failure of leptospirosis: nonoliguric and hypokalemic forms.
      A small proportion of survivors show persistent defects in tubular function and reduced glomerular filtration rates.
      • Daher Ede F.
      • Zanetta D.M.
      • Abdulkader R.C.
      Pattern of renal function recovery after leptospirosis acute renal failure.
      • Herath N.J.
      • Kularatne S.A.
      • Weerakoon K.G.
      • Wazil A.
      • Subasinghe N.
      • Ratnatunga N.V.
      Long term outcome of acute kidney injury due to leptospirosis? A longitudinal study in Sri Lanka.

      Infections in Patients With Pre-existing CKD in Asia Pacific

      Overview

      Infections remain common causes of morbidity, mortality, and hospitalization in patients with CKD, especially among those on dialysis therapy and after kidney transplantation. The pattern and outcome of infections are dependent on the local epidemiology and evolution of health care systems. Patients on hemodialysis (HD) therapy in resource-poor parts of the region with immature health care systems and lax regulatory standards are particularly vulnerable. Predisposing factors include late referral; reliance on central vein dialysis catheters, especially the uncuffed; frequent movement of patients between dialysis units; and poor adherence to infection control measures.
      • Jha V.
      • Chugh S.
      • Chugh K.S.
      Infections in dialysis and transplant patients in tropical countries.
      • Parameswaran S.
      • Geda S.B.
      • Rathi M.
      • et al.
      Referral pattern of patients with end-stage renal disease at a public sector hospital and its impact on outcome.
      • Jha V.
      • Chugh K.S.
      Posttransplant infections in the tropical countries.
      • Duong C.M.
      • Olszyna D.P.
      • McLaws M.L.
      Hepatitis B and C virus infections among patients with end stage renal disease in a low-resourced hemodialysis center in Vietnam: a cross-sectional study.
      Indian Society of Nephrology Working Group
      Guidelines for setting up hemodialysis in India.

      HBV and HCV Infections

      Despite increasing use of low-cost generic erythropoiesis-stimulating agents allowing a decrease in blood transfusion, infections with the 2 hepatitis viruses is a substantial problem in the dialysis population in many countries of the region. Patients with CKD are often referred late and therefore are not immunized against HBV, putting them at risk for contracting the disease in HD units.
      • Potsangbam G.
      • Yadav A.
      • Chandel N.
      • et al.
      Challenges in containing the burden of hepatitis B infection in dialysis and transplant patients in India.
      Moreover, serologic assays rather than sensitive nucleic acid–based techniques including polymerase chain reaction are still used for screening. This leads to underdiagnosis of infection in the window period, increasing the risk for horizontal transmission.
      In a recent study
      • Johnson D.W.
      • Dent H.
      • Yao Q.
      • et al.
      Frequencies of hepatitis B and C infections among haemodialysis and peritoneal dialysis patients in Asia-Pacific countries: analysis of registry data.
      of dialysis registries of 10 countries in Asia Pacific that included 201,590 patients, the hepatitis B surface antigen positivity rate ranged between 1.3% and 14.6%, and HCV seroprevalence varied between 0.7% and 18.1%. A significant proportion of HCV RNA–positive patients were seronegative. HBV prevalence was similar between PD and HD populations in China, Hong Kong, Malaysia, and Thailand, but higher in PD patients in Japan and Taiwan and lower in PD patients in South Korea. For HCV, the prevalence was higher in HD than PD patients across the region (7.9% vs 3%). The seroconversion rate was greater in HD patients (0.1 vs 0.03 per 100 patient-years at risk).
      In recent years, HCV infection has become a significant health threat in parts of Asia Pacific. A multicenter study from Vietnam of 8,654 patients found an HCV prevalence of 11% to 43%. Single-center studies from India have described prevalences of ∼50%, leading to calls for isolation of HCV-infected HD patients to that practiced for those with HBV infection.
      • Agarwal S.K.
      Prevalence and association of hepatitis C viremia in hemodialysis patients at a tertiary care hospital.
      • Agarwal S.K.
      Hemodialysis of patients with HCV infection: isolation has a definite role.
      In addition to increasing the risk for chronic liver disease, the hepatotropic viruses predispose to hepatocellular carcinoma and death.
      • Ohsawa M.
      • Kato K.
      • Itai K.
      • et al.
      Standardized prevalence ratios for chronic hepatitis C virus infection among adult Japanese hemodialysis patients.
      • Rahnavardi M.
      • Hosseini Moghaddam S.M.
      • Alavian S.M.
      Hepatitis C in hemodialysis patients: current global magnitude, natural history, diagnostic difficulties, and preventive measures.
      HCV positivity has been shown to be a risk factor for premature death in the Japanese HD population, as well as those in Australia and New Zealand.
      • Ohsawa M.
      • Kato K.
      • Itai K.
      • et al.
      Standardized prevalence ratios for chronic hepatitis C virus infection among adult Japanese hemodialysis patients.
      • Dunford L.
      • Carr M.J.
      • Dean J.
      • et al.
      Hepatitis C virus in Vietnam: high prevalence of infection in dialysis and multi-transfused patients involving diverse and novel virus variants.
      The availability of effective antiviral agents for HBV and more recently HCV are expected to change the management and outcomes in these patients.

      Tuberculosis

      The incidence of TB in patients with CKD is 10 to 15 times higher than that in the general population,
      • Jha V.
      • Chugh S.
      • Chugh K.S.
      Infections in dialysis and transplant patients in tropical countries.
      • Jha V.
      • Chugh K.S.
      Posttransplant infections in the tropical countries.
      increasing to more than 50-fold among those on dialysis therapy and after kidney transplantation.
      • Singh N.
      • Paterson D.L.
      Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.
      • Sakhuja V.
      • Jha V.
      • Varma P.P.
      • Joshi K.
      • Chugh K.S.
      The high incidence of tuberculosis among renal transplant recipients in India.
      About 7% to 10% of patients on maintenance dialysis therapy and 10% to 13% of transplant recipients develop overt TB. In some of the historic reports from the region, the overall mortality rate among organ transplant recipients with TB was 20% to 30%.
      • Singh N.
      • Paterson D.L.
      Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.
      • Sakhuja V.
      • Jha V.
      • Varma P.P.
      • Joshi K.
      • Chugh K.S.
      The high incidence of tuberculosis among renal transplant recipients in India.
      There are a number of issues of management of TB in the region. These include difficulties making a timely diagnosis of both active and occult TB, access to modern methods of detection and management of a potential transplant recipient with latent TB,
      • Pai M.
      • Denkinger C.M.
      • Kik S.V.
      • et al.
      Gamma interferon release assays for detection of Mycobacterium tuberculosis infection.
      minimizing the risk for donor-derived TB transmission to transplant tourists,
      • Morris M.I.
      • Daly J.S.
      • Blumberg E.
      • et al.
      Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report.
      dealing with the increasing prevalence of multidrug-resistant TB,
      • Matteelli A.
      • Centis R.
      • D'Ambrosio L.
      • Migliori G.B.
      Multidrug-resistant tuberculosis today.
      and managing the interaction between anti-TB agents and posttransplantation immunosuppression. Mortality from TB can be almost eliminated by keeping a high index of suspicion, insisting on invasive investigations to establish the diagnosis, and instituting therapy promptly.
      • Jha V.
      • Sakhuja V.
      • Gupta D.
      • et al.
      Successful management of pulmonary tuberculosis in renal allograft recipients in a single center.
      Neither Mantoux testing nor the newer interferon γ release assays have been found useful for identifying latent TB before transplantation in endemic regions.
      • Shankar M.S.
      • Aravindan A.N.
      • Sohal P.M.
      • et al.
      The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: tuberculin test and the risk of post-transplant tuberculosis.
      New anti-TB drug regimens that exclude rifampicin have simplified the problem drug interactions altering the concentration of calcineurin inhibitors in transplant recipients.
      • Jha V.
      • Sakhuja V.
      Rifampicin sparing treatment protocols in posttransplant tuberculosis.

      Fungal Infections

      In tropical countries, patients with CKD are at increased risk for fungal colonization because of the hot and humid climate, poor hygiene, and common use of broad-spectrum antibiotic therapy. A significant proportion develop clinical disease. The disease pattern, organ involvement, and presentation are influenced by stage of CKD, type of RRT (HD, PD, or kidney transplantation), and the local mycologic flora.
      • Jha V.
      • Chugh S.
      • Chugh K.S.
      Infections in dialysis and transplant patients in tropical countries.
      • Jha V.
      • Chugh K.S.
      Posttransplant infections in the tropical countries.
      The most common endemic mycoses in Oceania are histoplasmosis, penicilliosis, and sporotrichosis, whereas the dominant infections in tropical countries are caused by saprophytic and opportunistic fungi such as Candida, Aspergillus, and Zygomycetes species.
      • Slavin M.A.
      The epidemiology of candidaemia and mould infections in Australia.
      • Slavin M.A.
      • Chakrabarti A.
      Opportunistic fungal infections in the Asia-Pacific region.
      There is a high (10%-14%) prevalence in PD patients of peritonitis caused by Candida species reported in India.
      • Prasad K.N.
      • Prasad N.
      • Gupta A.
      • Sharma R.K.
      • Verma A.K.
      • Ayyagari A.
      Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis: a single centre Indian experience.
      • Prasad N.
      • Gupta A.
      Fungal peritonitis in peritoneal dialysis patients.
      Similarly, mucocutaneous fungal infections are frequent in kidney transplant recipients, seen in 60% to 72%. The organisms responsible include tinea corporis, tinea cruris, and tinea versicolor (55%-65%), followed by Candida (7%-9%) and Cryptococcus species (0%-1%). The incidence of tissue-invasive fungal infections among kidney transplant recipients is 4% to 7%.
      • Chugh K.S.
      • Sakhuja V.
      • Jain S.
      • et al.
      High mortality in systemic fungal infections following renal transplantation in third-world countries.
      • John G.T.
      • Mathew M.
      • Snehalatha E.
      • et al.
      Cryptococcosis in renal allograft recipients.
      Overall, aspergillosis remains the most frequently reported invasive mold infection in patients with CKD and posttransplantation patients within Asia Pacific.
      • Slavin M.A.
      The epidemiology of candidaemia and mould infections in Australia.
      • Kiertiburanakul S.
      • Thibbadee C.
      • Santanirand P.
      Invasive aspergillosis in a tertiary-care hospital in Thailand.
      • Oh M.D.
      • Park S.W.
      • Kim H.B.
      • et al.
      Spectrum of opportunistic infections and malignancies in patients with human immunodeficiency virus infection in South Korea.
      A high prevalence of zygomycosis has been reported from India.
      • Chakrabarti A.
      • Das A.
      • Sharma A.
      • et al.
      Ten years' experience in zygomycosis at a tertiary care centre in India.
      Delayed diagnosis because of the lack of specialized laboratories and failure to use invasive diagnostic tests increase the morbidity and mortality.

      Challenges and Future Directions

      Because of the link between diabetes, hypertension, and cardiovascular disease, CKD has been categorized under the broad heading of noncommunicable diseases.
      • Tonelli M.
      • Agarwal S.
      • Cass A.
      • et al.
      How to advocate for the inclusion of chronic kidney disease in a national noncommunicable chronic disease program.
      However, this paradigm might be inappropriate in large parts of the world, including Asia Pacific. We argue that the direct and indirect contribution of infection has a major impact on the onset and course of CKD in the region and deserves the attention of the research community and public health policymakers. The WHO has described several of the infections highlighted in this review as “neglected diseases,” meaning they receive less attention from the scientific community and pharmaceutical industry.

      World Health Organisation. Neglected tropical diseases. http://www.who.int/neglected_diseases/diseases/en/. Accessed July 12, 2015.

      Infection control in large parts of Asia Pacific is limited by poverty, high population density, inadequate sanitary facilities, low uptake of vaccines, indiscriminate antimicrobial use leading to multidrug-resistant organisms, isolation from health care access, and periodic disasters and wars.
      • Jha V.
      ESRD burden in South Asia: the challenges we are facing.
      In large parts of Asia Pacific with growing economies, land clearance and deforestation in the name of development have led to large-scale disruptions and loss of biodiversity, leading to the emergence of new strains of Hantaan viruses, dengue viruses, multidrug-resistant Escherichia coli, and artemisinin-resistant Plasmodium species, all of which have implications for kidney disease.
      • Lu Y.
      • Essex M.
      • Roberts B.
      Emerging Infections in Asia.

      Davis JR, Lederberg J. Emerging infections in Asia and the Pacific -emerging infectious diseases from the global to the local perspective. Forum on Emerging Infections, Board on Global Health. Washington, DC: National Academies Press (US); 2001.

      Increased population mobility reduces the likelihood of geographic containment. Global warming and climate change are expected to have an adverse effect on the ecosystem, affecting the availability of clean air, potable water, sanitation facilities, sufficient food, and safe shelter. As a consequence, there has been a sharp increase in the number of outbreaks of infectious diseases in Asia Pacific
      • Morand S.
      • Jittapalapong S.
      • Suputtamongkol Y.
      • Abdullah M.T.
      • Huan T.B.
      Infectious diseases and their outbreaks in Asia-Pacific: biodiversity and its regulation loss matter.
      (Fig 5).
      Figure thumbnail gr5
      Figure 5Increase in total outbreaks and total number of infectious diseases causing outbreaks since 1950 in Asia Pacific countries.
      Reproduced from Morand et al.
      • Morand S.
      • Jittapalapong S.
      • Suputtamongkol Y.
      • Abdullah M.T.
      • Huan T.B.
      Infectious diseases and their outbreaks in Asia-Pacific: biodiversity and its regulation loss matter.
      The paucity of good-quality data limits accurate assessment of the impact of infections on CKD in the region. Most developing countries in the region do not have a systematic process for collecting data for patients with chronic kidney failure and earlier stages of CKD. Proper evaluation of the impact of kidney involvement on the infection cycle is needed. It is possible that early recognition and aggressive management of kidney complications might improve short- and long-term patient outcomes in patients with infections. This knowledge gap can only be bridged by prospective studies with particular attention to infections. Nephrologists need to establish linkages with infectious disease research groups and government infection surveillance and control programs. Infectious disease databases should collect data on the pattern and severity of kidney disease and its impact on short- and long-term outcomes, in particular the risk for CKD and its complications.
      Strategies to combat infection in Asia Pacific need to take account of the local geography and climate. A cooperative approach between different countries of the region is also needed. For example, the failure of malaria eradication programs in India is explained in part by the reintroduction of the vector and organisms from neighboring countries, where similar eradication programs were not implemented simultaneously.

      National Vector Borne Disease Control Programme. Annual Report 2014-15. Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India. http://nvbdcp.gov.in/. Accessed July 12, 2015.

      Lack of safe drinking water and adequate sanitation remain major threats to kidney health. The important contribution of repeated clinical or subclinical episodes of kidney injury related to recurrent diarrheal illnesses, especially in children and in agricultural workers who work all day in a hot and humid environment, has not been adequately studied. Lessons must be learned from the descriptions of Mesoamerican nephropathy from Central America,
      • Correa-Rotter R.
      • Wesseling C.
      • Johnson R.J.
      CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.
      where some local governments have provided shaded “rest areas” and instituted mandatory “water breaks” for these workers.
      • Stix G.
      The Riddle of What Is Killing Thousands of Central American Cane Workers.
      Inexpensive technology is needed for purifying water in rural areas to make it potable. Health education will help people change their drinking habits and will encourage hand washing and cleaning raw fruits and vegetables gathered from potentially contaminated fields. The solutions require changes in all aspects of health systems. Close collaboration is needed between physicians, public health professionals, policy makers, social activists, and the media. The successful eradication of smallpox from the globe and the near eradication of polio are encouraging examples that suggest that despite huge obstacles, these goals can be achieved.

      Acknowledgements

      Support: Dr Jha has grant support from the Department of Biotechnology, Government of India, and the Indian Council of Medical Research.
      Financial Disclosure: Dr Jha has received research grants from Baxter International and GlaxoSmithKline. The other author declares that he has no relevant financial interests.
      Peer Review: Evaluated by 2 external peer reviewers, the Feature Editor, and the Editor-in-Chief.

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