Infections and the Kidney

Abstract

Infections of the kidney and urinary tract are a common cause of morbidity, and sometimes mortality, especially in young women. The responsible pathogens include bacteria, viruses, protozoa, parasites, and fungi. The clinical nature of the infection can be different in the immunosuppressed, in the setting of kidney transplantation, and in other conditions, including vasculitis, glomerulopathy and cancer. Some infections can lead to systemic immune activation, which can in turn lead to kidney disease.

FormalPara Clinical Scenario 1

A 71-year old woman with end-stage kidney disease (ESKD) secondary to diabetic nephropathy, maintained on twice-weekly haemodialysis (HD), was admitted for management of profuse rectal bleeding secondary to diverticulitis. She was catheterised and transfused with a unit of packed red cells. A week into her admission, she started vomiting and became listless. Her temperature and vital signs were normal. Urinalysis revealed a positive leukocyte esterase, and her urine bag and tubing acquired a purple colour (Fig. 14.1a). Urine samples obtained from the urine bag and urethral catheter did not have the purple coloration (Fig. 14.1b and c). The urethral catheter was removed and her urine cultured, yielding. Escherichia coli sensitive to Ceftazidime. She was treated with intravenous ceftazidime, with resolution of her symptoms, and a negative urine culture thereafter.

Fig. 14.1

The purple urine Bag Syndrome (PUBS) (a) shows purple discoloration of urine in the patient’s catheter bag; (b) shows a catheter urine sample; (c) shows a urine bag sample. The purple urine bag syndrome occurs when colonic bacteria degrade tryptophan to indole. Indole is converted to indole sulphate in the portal circulation and once filtered into the urine is catabolized by indole sulphatase and bacteria to indigo and indirubin. Both pigments attach to the urine bag to stain it purple, though the urine retains its usual amber yellow colour [1]

FormalPara Clinical Scenario 2

An 11-year-old female, presented to the emergency department (ED) with a 2-week history of fever. For the previous 6 days, she had noted that her urine had become brown (sometimes referred to as “coke-coloured”) followed by a reduced urine output, and generalized body swelling. Two days before admission she had become short of breath, and a few hours before she attended the ED she had suffered a seizure. She had had a skin infection 3 weeks prior to her symptoms. On examination, she was pale, febrile, in respiratory distress, with an impaired state of consciousness, with a Glasgow coma score of 8/15. Her temperature was 37.8 °C, her respiratory rate 38 breaths/min, BP 160/110 mmHg, and pulse 110/min. She had significant bilateral pitting leg oedema. It was also noted that she had multiple bilateral hyperpigmented macular skin lesions. She had demonstrable ascites and fine bilateral crepitations. Catheterization revealed the brown urine, with a urine flow rate of 0.3 mL/kg/h. Urinalysis showed blood, protein, leukocytes, and microscopy revealed red cell casts. Blood results: Sodium: 122 mmol/L, potassium: 5.6 mmol/L, HCO₃ 12.4 mmol/L, chloride: 84.4, iCa: 1.01, BUN: 63.3 mmol/L, creatinine: 884 μmol/L, haemoglobin: 8.3 g/dL, leukocytosis with neutrophila of 78%; ESR: 125 mm/h and qualitative ASO titre: elevated/positive, C3: not available. Ultrasonography: kidneys measured 11 × 4 cm and 10.8 × 3.6 cm, with increased echogenicity and moderate obliteration of sinoparenchymal differentiation.

A diagnosis of acute kidney injury (AKI) with hypertensive/uraemic encephalopathy secondary to post-streptococcal glomerulonephritis (PSGN) was made.

She had 3 sessions of haemodialysis, IV furosemide, fluid restriction, amlodipine, IV Sultamicillin tosylate initially and later, oral amoxicillin/clavulanate potassium.

The patient was followed-up for 4 months; her kidney function improved to an eGFR of 96 mL/min/1.73 m², although she continues to have dipstick haematuria.

Introduction

Infections cause kidney disease via diverse mechanisms, including by (1) direct tissue invasion; (2) indirectly by immune-mediated mechanisms which lead to glomerulonephritis; (3) acute kidney injury (AKI); (4) less common is nephrotoxic damage which occurs with medications and diagnostic procedures as part of patient management. The manifestations of disease depend on the patient’s health status/immune defense mechanisms, the micro-organism, and numerous genetic and environmental factors. The different microorganisms that will be discussed in this chapter are listed below:

• Bacteria

  • 1. Direct Injury To The Kidney

    • Urinary tract infections

    • Reflux nephropathy

    • Mycobacteria

      • Tuberculosis

      • Leprosy

    • Leptospirosis

  • 2. Indirect or Immune-mediated Damage to the Kidney

    • Bacterial Infection-Related Glomerulonephritis

    • Post-Streptococcal GN (PSGN)

  • 3. Kidney Injury as part of Ongoing Sepsis

  • 4. Nephrotoxic Damage from Medications

• Viruses

  • Dengue

  • Hantavirus

  • Ebola

  • Parvovirus

  • Polyoma virus

  • Cytomegalovirus CMV

  • Varicella

  • Hepatitis viruses: HEV, HAV, HBV, HCV

  • Human immunodeficiency virus HIV

  • Severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]

• Protozoa and Parasites

  • Malaria

  • Schistosomiasis

• Fungi

Bacterial Infections and Kidney Disease

A large number of bacterial infections cause kidney disease, via the mechanisms mentioned above; they include Gram-positive and negative cocci, Gram-positive and negative bacilli and coccobacilli, some not readily Gram-stained organisms such as Mycobacterium species and others like Mycoplasma pneumonia and Chlamydia pneumonia.

Mechanisms of Bacterial Infection-Related Kidney Diseases

Direct Injury to the Kidney

Urinary Tract Infections (UTIs)

Urinary tract infections (UTIs) are very common and caused mainly by gram negative bacteria. They affect >150 million people each year worldwide; 40–50% of women and 5% of men will invariably have an episode of UTI at least once in their life [2]. The incidence is highest in adolescent and childbearing females, peaking during the years of maximum sexual activity (18–39 years) [3]; this age-group is 30 times more likely to have UTI than their male counterparts [4]. However, the incidence of UTI increases in men >60 years, mainly because of prostatic obstruction, and approaches the incidence of UTI in women.

Epidemiology: Though community-acquired uncomplicated UTIs account for most infections, the prevalence of healthcare-acquired UTIs ranges from 12.9% in the US and 19.6% in Europe to 24% in developing countries [5]. Predisposing factors such as age, health status, catheterization and immunosuppression determine the dynamics of the infection. For example, whereas non-catheterized persons are more likely to suffer UTIs caused by a single bacterial species, catheterization/structural abnormalities predispose to UTIs caused by multiple bacterial species. In Clinical Scenario 1, the patient had 4 risk factors for UTI: age, female gender, immunosuppression (immune paresis related to her diabetes mellitus and uraemia), and catheterization [1].

Bacteria ascend through the urethra to the bladder, initiating symptomatic or asymptomatic bacteriuria, and subsequently reach the kidneys to cause pyelonephritis (ascending infection). Less commonly, infection can arise from haematogenous spread (descending infection).

UTIs are classified using several criteria: They are categorized using complication status, as listed below and in Tables 14.1, 14.2, 14.3, 14.5, where management is outlined for each category.

Table 14.1 Diagnosis & management of asymptomatic bacteriuria and uncomplicated UTIs

Table 14.2 Diagnosis & management of complicated UTIs, recurrent UTIs and urosepsis

Table 14.3 Investigations and management of chronic tubulo-interstitial nephritis (TIN), genitourinary TB and leptospirosis

Asymptomatic bacteriuria: Is defined as significant bacteriuria in a midstream urine (MSU) specimen in people with no relevant genitourinary symptoms, with uro-pathogens >10⁵ CFU/mL in two consecutive samples in females, or a single sample in males [6, 7].

Uncomplicated UTIs: Consist of community-acquired cystitis (lower urinary tract infection with symptoms of dysuria, frequent and urgent urination and suprapubic pain) and pyelonephritis (infection of the renal parenchyma and pelvi-calyceal system with symptoms of fever and flank pain). Figure 14.2 and Table 14.1 outline an algorithm for management of uncomplicated UTIs [9].

Fig. 14.2

Algorithm for the approach to management of acute uncomplicated cystitis (adapted from IDSA Guidelines [9]). UTI urinary tract infection

Complicated UTIs: Infection associated with a structural/functional genitourinary tract anomaly or underlying diseases that increase risk of worse outcome [8]; such as: indwelling urinary catheters, urinary obstruction, anatomical abnormalities, peri-operative urinary tract infections, including kidney transplantation (Table 14.2).

Recurrent UTIs: Defined as at least three episodes of uncomplicated infection confirmed by urine culture over a 12-month period or 2 episodes over 6 months. They include lower and upper UTIs. The two types of recurrent UTI are:

Relapse—defined as recurrent UTI involving the same organism(s) after adequate therapy; and

Reinfection—defined as recurrent UTI caused by an infection that has been treated and subsequent repeat infection with the original bacteria or a second or new isolate [6]. Figure 14.3 illustrates an algorithm for management of recurrent UTIs [11].

Fig. 14.3

Algorithm for management of recurrent uncomplicated urinary tract infections [11]. The target patient group is of otherwise healthy adult females with recurrent uncomplicated UTIs; Patients with complicating factors such as listed below are outside the scope of the pathway: (1) Anatomic or functional abnormality of the urinary tract, (2) Immunocompromised host, (3) Multi-drug resistant bacteria. MCS microscopy, culture & sensitivities, TMP-SMX trimethoprim-sulfamethoxazole, UTI urinary tract infection

Complications of UTIs include:

Urosepsis: Complicated and severe UTI occurring in the setting of a systemic inflammatory response syndrome (SIRS). It causes multiple organ dysfunction (acute respiratory distress syndrome, acute kidney injury (AKI), and disseminated intravascular coagulopathy (DIC)). In 20–30% of patients with sepsis, the urinary tract is the source; the estimated global mortality rate for sepsis is about 30–40% [18]. The management of urosepsis is outlined in Table 14.2. Predisposing factors include urological anomalies, stones, urinary tract obstruction and, in male children, posterior urethral valves.

Other complications of UTI include kidney abscess, perinephric abscess, infected hydronephrosis/pyonephrosis, acute focal bacterial nephritis, emphysematous and xanthogranulomatous pyelonephritis, and malakoplakia.

Reflux Nephropathy

Reflux nephropathy has replaced the term ‘Chronic pyelonephritis’, a term that has become obsolete.

Aetiology

Reflux nephropathy is a result of an abnormality at the uretero-vesical junction. The musculature of the lowermost part of the normal ureter prevents reflux of urine from the bladder into the ureter. Failure at the vesico-ureteric junction means that urine passes up the ureter on bladder emptying, and in some patients there is free reflux, even when the bladder is not contracting. This is known as vesico-ureteric reflux (VUR).

Background

Until the 1970s, reflux nephropathy was known as 'chronic pyelonephritis', and was thought to be a chronic progressive condition. It was also thought that each urinary infection was capable of producing a scar, and furthermore that reflux nephropathy caused hypertension. In the 1970s, Dr. Jean Smellie challenged the nephrological world to show that new scars could arise in adulthood: no such developing scars were found. It became clear that the scarring process took place mainly in the first 5 years of life, and that the change in kidney shape and the ‘development of scars’ during teenage years was simply the result of normal growth of the unaffected kidney tissue, thereby making the existing scarred elements more prominent.

Clinical Management

The abnormality is sometimes first detected in utero, when urine may be seen entering the foetal ureter during micturition. This will enable the neonatologist to take appropriate measures to prevent urinary infection in the neo-natal period.

A proportion of young children will present with a febrile illness that may not be recognised initially as a urinary tract infection. It is important to establish such a diagnosis, so that measures can be implemented to keep the urine sterile; this involves keeping the bladder empty. If a significant volume of urine refluxes up the ureter(s), there will inevitably be urine in the bladder after micturition (residual urine). One method in older children is to advise double micturition: the volume passed on the second occasion will give some idea of the scale of the reflux. If necessary, the bladder can be emptied again to be sure that the bladder is empty.

Investigations

VUR is diagnosed by the demonstration of backflow of urine into the upper renal tract(s). Historically, the diagnosis has been made by micturating cystourethrography, which provides good anatomical detail, but does require bladder catheterisation. For older children, indirect radionuclide cystography is preferable, as it does not require catheterisation.

Clinical Features in Adults

Typically in adults, the signs of reflux nephropathy will be found as an incidental finding on abdominal imaging: there will be one or more cortical scars overlying an anatomically distorted calyx, involving one kidney or both. In most cases the vesico-ureteric reflux will have remitted, and the urine will be sterile. In the absence of other factors (such as hypertension), the kidney function will remain relatively stable, and the number of adults requiring kidney replacement therapy (KRT) is small. Chronic kidney disease in this setting tends to progress when there is significant proteinuria (secondary FSGS), when hypertension is not well controlled, or when UTIs continue to recur.

Practice Point 1 Congenital Abnormalities of the Kidneys and Urinary Tract [CAKUT]

CAKUT encapsulates the various congenital urinary tract abnormalities that—although arising in childhood—sometimes present in adulthood, including vesicoureteric reflux. They include duplex pelvi-calyceal systems, horseshoe kidney, pelvic kidney, mega-ureter, posterior urethral valves and a number of other uncommon disorders [19]

Mycobacterial Infections

Tuberculosis

Tuberculosis (TB) has a world-wide distribution, but is especially common in developing countries. The highest incidence rates are in sub-Saharan Africa and in the region stretching from the Indian subcontinent to South-East Asia and the Western Pacific (Fig. 14.4). In 2018, ten million people became ill with TB; 1.5 million of them died [21]. The emergence of multi-drug resistant TB as a co-infection with HIV/AIDs has made TB a major public health challenge. Extra-pulmonary TB (ETB) is estimated to occur in 10–34% of patients who do not have HIV, compared to about 50–70% in patients with HIV/AIDs [22].

Fig. 14.4

Global Incidence of Tuberculosis in 2020; reproduced with permission from the World Health Organisation (WHO) [20]

Kidney involvement occurs as part of a disseminated infection, or as localized genitourinary disease. The disease causes extensive papillary necrosis and cavities, destroying the kidney parenchyma, and extending to the collecting system, causing obstructive uropathy and kidney impairment. Management of genitourinary TB is outlined in Table 14.3. Glomerulopathy (like focal proliferative glomerulonephritis) and amyloidosis can occur from TB occurring in any part of the body [23]. Patients on KRT (haemodialysis, peritoneal dialysis and following kidney transplantation), and those on immunosuppressive therapy are particularly prone to TB infection.

Classical Uro-Genital Tuberculosis (UGTB)

Clinical Features

Uro-genital tuberculosis (UGTB), which is estimated to affect 6–8% of patients with TB, is easy to overlook. Systemic symptoms are uncommon. Often, lower urinary symptoms draw attention to the urinary tract, and typically there is pyuria, but no growth on culture using standard media—a so-called ‘sterile’ pyuria. Other reasons for the finding of a sterile pyuria are listed in Table 14.4.

Table 14.4 Causes of a ‘sterile’ pyuria

The suspicion of TB may be aroused when the symptoms are not relieved by conventional antibiotics, however, there are sometimes suggestive symptoms - back, flank and suprapubic pain, macroscopic haematuria, frequency, and nocturia. Unlike newly-presenting TB, fever, weight loss and night sweats are unusual, and only a third of patients have an abnormal chest X-ray.

Investigations

Abdominal X-ray may show calcification, and urinary tract ultrasound is likely to show focal fibrosis and/or scarring—sometimes severe—as well as calcification in kidneys and bladder (thimble bladder).

Treatment

For newly presenting TB, the World Health Organisation (WHO) recommends oral treatment for 6 months, commencing with 4 drugs, that should include rifampicin and isoniazid (Table 14.3). In patients with kidney dysfunction, careful attention needs to be taken regarding the dosing of the drugs prescribed.

Tuberculous Interstitial Nephritis

There have been a number of reports of interstitial nephritis with granuloma formation, and there has been a suspicion that TB has been responsible. Some patients have had TB elsewhere and hypersensitivity to tuberculin. An early report described three such patients [24]. More recently, it has become clear that such patients cannot reliably be distinguished from sarcoidosis, and it has been suggested that a trial of anti-tuberculous drugs can be justified [25].

End-Stage Kidney Disease

Once TB is recognized and treated, it is likely that kidney replacement therapy (KRT) can be avoided. There are very few data on the frequency of TB as a cause of end-stage kidney disease (ESKD), but there is one report using data from the European Dialysis and Transplant Registry. Analysis of data from 5 years between 1984 and 1991 showed that the primary kidney diagnosis was classified as kidney TB [code 91] in 0.5–1.0% of patients starting KRT [26].

Leprosy

The incidence and prevalence of leprosy has been falling slowly over recent years but there has been little change in the global extent of the disease. It remains more or less confined to middle- and low-income countries, especially Brazil and the countries of the Indian sub-continent (Fig. 14.5).

Fig. 14.5

Leprosy new case detection rates 2016 reproduced with permission from the World Health Organisation (WHO) [27]

Clinical Features

Kidney involvement is common in leprosy, and it is now clear that it is the multi-bacillary (lepromatous) form that is most closely associated with kidney disease. A study of 199 autopsies from Brazil showed that 144 [72%] had kidney lesions. Sixty-one of the 144 (42.4%) showed amyloidosis [28]. This included 36% of the lepromatous group but only 5% of the tuberculoid and borderline cases. It was noted that during flare-ups of erythema nodosa leprosum, the serum creatinine would tend to rise.

Silva et al. reported on 16 studies of kidney disease in patients with leprosy [29]. Excluding 10 studies where there was either no biopsy or fewer than five patients, there were 354 biopsies in 6 studies. All six mentioned amyloidosis as the prominent diagnosis; many of the patients described had proteinuria.

There are a few reports of glomerulonephritis among patients with leprosy but there is no consistent pattern, and such associations are as yet unproven.

Treatment

The WHO recommends a 3-drug regimen for multi-bacillary [lepromatous] leprosy - rifampicin, clofazamine and dapsone. The recommendation for pauci-bacillary leprosy [tuberculoid] is a 2-drug regimen - rifampicin and dapsone. Rifampicin and dapsone do not require dose reduction in patients with reduced GFR; for Clofazimine, the UK British National Formulary (BNF) states “Use with caution”.

Leptospirosis

Leptospirosis is a zoonotic disease, which is re-emerging as an infectious disease of global public health importance. It affects approximately 1.03 million people annually and it is projected to rise further as extreme climatic conditions and global warming increase [30].

Leptospirosis Kidney Disease: Acute leptospirosis causes multiple organ dysfunction including AKI. A long-term follow-up study of leptospirosis AKI patients in Sri Lanka found that 9% of them developed an early stage of CKD [31], indicating that leptospirosis AKI can result in CKD/ESKD.

Asymptomatic carriers harbor the Leptospira spirochaete in the kidney where they colonize the proximal tubule resulting in chronic tubulointerstitial nephritis and fibrosis causing insidious progression to CKD. It is thus suggested that asymptomatic exposure to leptospira infection carries the risk for CKD. Histologic findings in leptospirosis kidney disease are tubulointerstitial nephritis, interstitial fibrosis, and tubular atrophy. Proximal tubule dysfunction and hypokalaemia are seen also in adult male patients with leptospirosis. These bear a characteristic similarity to findings in CKD of unknown aetiology (CKDu), a form of CKD that clusters amongst farmers who work in hot dry climates. Table 14.3 outlines the diagnosis and management of leptospirosis.

Practice Point 2 Leptospirosis Kidney Disease and CKDu Overlap

Leptospirosis kidney disease and CKDu tend to affect similar populations in similar geographical regions. The similarity of their kidney pathologies has put leptospirosis as a priority candidate for some patients with CKDu. It is postulated that secondary injury from heat stress and dehydration worsens the kidney injury. Thus, leptospira infection causes primary kidney disease or acts as a CKD susceptibility factor.

Indirect or Immune-Mediated Damage to the Kidney

Indirect bacteria-related damage to the kidney occurs as inflammation of the glomerulus due to immune complex deposition. Infection related GN (IRGN) was previously known as postinfectious GN (PIGN); the prototype, poststreptococcal GN (PSGN) commonly occurs in children. PIGNs are mainly caused by streptococcal infections (28–47%), while staphylococcal and gram-negative infections account for 12–24% and 22%, respectively [32]. Other infections, such as bacterial endocarditis and shunt infections can also cause a PIGN.

Bacterial Infection-Related Glomerulonephritis (B-IRGN)

B-IRGN is described as kidney dysfunction from glomerular inflammation, with evidence of ongoing bacterial infection, unlike PSGN which occurs weeks after the infection. The incidence of IRGN, though decreasing, constitutes about 5% of all glomerular diseases [33]. It occurs more frequently in developing countries. It is commoner in adults, with much higher rates in the elderly and patients with diabetes. Other risk factors include malignancy, malnutrition, chronic infections (HIV and TB), and prosthetic heart valves. IRGN can result from infections occurring in any part of the body (skin, upper and lower respiratory tract, heart, urinary tract, bone). Many bacterial species can be involved, but staphylococcal species are more common in adults and the elderly.

The most common presentation is an acute nephritic syndrome, with or without impaired kidney function. B- IRGN has poorer prognosis than PSGN, and also has a poorer prognosis in adults than in children [32, 33]. Early detection and treatment of infections can prevent kidney involvement (Table 14.5).

Table 14.5 Investigations and management of other bacterial infection-related kidney diseases: bacterial infection-related glomerulonephritis (B-IRGN), post-streptococcal glomerulonephritis (PSGN) and nephrotoxic damage

Post-streptococcal GN (PSGN)

PSGN is diagnosed in a patient with antecedent streptococcal infection who presents with acute GN; for streptococcal sore-throat, the nephritis follows 7–15 days afterwards, while for skin infections 4–6 weeks after (see Clinical Scenario 2). PSGN is an immune-mediated GN triggered by immune-complex deposits in the sub-endothelium and mesangium comprising of bacterial antigens (glyceraldehyde-3-phosphate dehydrogenase and streptococcal pyrogenic exotoxin B).

The most common clinical manifestation is acute nephritic syndrome which lasts <2 weeks. Other less common manifestations are asymptomatic proteinuria, nephrotic syndrome or rapidly progressive GN. The prognosis in children is excellent, but in the elderly, there is an associated mortality of up to 20% [32]. The long-term prognosis is worse in patients who have persistent proteinuria >6 months. Clinical Scenario 2 illustrates a typical presentation of severe PSGN, in a patient in Nigeria, although many patients are seen with a less severe presentation. The management of PSGN is outlined in Table 14.5.

Kidney Injury as Part of Ongoing Sepsis

One of the commonest ways by which bacterial infections cause kidney dysfunction is through AKI, which occurs as part of multi-organ dysfunction following sepsis from any focus. About 20% of very ill patients have irreversible kidney injury from acute cortical necrosis and many more (40%) progress to CKD following incomplete recovery [34]. Often, these patients have pre-existing mild-moderate CKD from diverse causes. AKI incidence increases according to severity of sepsis, from 4.2% in mild sepsis to 22.7% in severe sepsis and rising to 52.8% in septic shock [35]. Table 14.3 outlines the management of sepsis/urosepsis.

Nephrotoxic Damage from Medications, Used in Patients with Infection

Drugs commonly cause kidney damage and drug-induced nephrotoxicity (DIN) occurs in 14%–26% and 16% of AKI in adult and paediatric populations respectively [36]. It is commoner in older patients, who are more likely to have diabetes and cardiovascular disease and are consequently exposed to several medications and diagnostic procedures that can harm the kidney. Antibiotics and other medications like non-steroidal anti-inflammatory drugs (NSAIDs) useful in treatment of bacterial infections are known to be nephrotoxic. Table 14.6 shows the common mechanisms leading to drug-induced nephropathy and some implicated medications.

Table 14.6 Mechanisms of drug-induced nephropathy

Factors that increase the risk of nephrotoxicity include intravascular volume contraction, age > 60 years, diabetes, use of multiple nephrotoxins, heart failure, sepsis, underlying kidney impairment.

Prevention, vigilance, recognition and early intervention are key to successful outcome [37]. Awdishu and Mehta proposed the 6R approach (Risk assessment, early Recognition, targeted Response, timely Renal support and Rehabilitation coupled with Research) for management of DIN [38]. Table 14.5 outlines the investigations and management of infection-related kidney damage due to nephrotoxic damage.

Viral Infections and the Kidney

Viral infections can cause kidney damage through direct viral invation, immune mediated damage, haemodynamic instability, haemolysis, rhabdomyolysis, and cytokine storm, amongst other mechanisms. Table 14.7 summarises the viruses associated with kidney damage, the mechanism of injury, typical kidney involvement and management of the condition.

Table 14.7 Kidney involvement in viral infections

Dengue Virus

Dengue virus (DV) infection causes widespread capillary leakage, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) resulting in ischaemic acute tubular necrosis. Direct viral cytopathic effects, and immune complex injury, haemolysis and rhabdomyolysis are other mechanisms of kidney disease [39]. Clinical manifestations vary from asymptomatic urinary abnormalities to severe acute kidney injury(AKI) in native and allograft kidneys [40]. Proteinuria occurs in over 70%, whereas haematuria is less frequent in DHF. Kidney involvement occurs during acute infection, with detectable anti-DV antibodies and viral nucleic acid in plasma. AKI is more frequent in DHF and DSS and is associated high mortality. Kidney biopsy may reveal acute tubular necrosis, interstitial nephritis and various immune complex GN, as shown in Table 14.7. DV antigen may be detected in tubular epithelial cells [41]. Management is supportive with fluid resuscitation, control of metabolic derangements and management of coagulopathies. Kidney outcomes are good; however, proteinuria and haematuria may persist after recovery of AKI [42].

Hantavirus

Hantavirus(HV) infection is associated with increased vascular permeability and haemorrhage leading to organ dysfunction, with kidney involvement reported in 30–60% of cases, especially in hantavirus haemorrhagic fever with renal syndrome(HFRS) [43]. Kidney disease occurs in the course of active infection from direct viral invasion of tubular epithelial cells, glomerular endothelial cells and podocytes [44]. Systemic inflammatory and immune complex deposition may also contribute to kidney disease. Oliguric AKI with haematuria and sub-nephrotic proteinuria, followed by polyuria is the usual clinical presentation in HFRS. Milder forms of kidney dysfunction may be seen in the other Hanta virus syndromes. Kidney histopathology shows acute haemorrhagic interstitial nephritis with mononuclear cell infiltrates (CD8+ T-lymphocytes and macrophages), tubular necrosis and congestion of peritubular capillaries, especially in the outer medulla [45]. Glomerular lesions have also occasionally been reported; (see Table 14.7). Management is mainly supportive with antipyretics, fluid resuscitation, control of electrolyte disorders, vasopressors and KRT when indicated. Kidney recovery is usual; however, hypertension, cardiovascular disease, hypopituitarism and chronic kidney disease of unknown aetiology have been reported in those who recover [46, 47].

Ebola Virus

Ebola infection is marked by uncontrolled viral replication, which results in excessive proinflammatory responses, endothelial dysfunction, and dysregulation of the coagulation cascade, haemorrhage and subsequently severe organ dysfunction. Viral invasion of tubular and endothelial cells, systemic complications of the infection, and bacterial and malarial super infection result in kidney involvement [48]. Acute kidney injury is the main manifestation in 20–50% of cases. AKI is multifactorial, as outlined in Table 14.7. Kidney biopsy is not routine for diagnosis; however, acute tubular necrosis and degeneration with interstitial oedema and mild cellular infiltrates have been reported on kidney histology [49]. Aggressive fluid resuscitation and usual care for AKI, including KRT is the mainstay of management, with particular consideration of staff safety [50].

Parvovirus

Symptomatic parvovirus B(PVB) infection occurs in 2–12% of patients in the first year of kidney transplantation, with 10% of these developing allograft dysfunction [51]. PVB kidney disease may also occur in native kidneys of immunocompetent individuals. Direct invasion of kidney tissue and immune-mediated kidney injury are the main disease mechanisms [52]. Acute nephritic syndrome with hypocomplementaemia, following a prodrome of rash, fever, and arthritis is frequent. Nephrotic syndrome or chronic kidney disease is seen in sub-acute infection; and aplastic crisis may follow the nephrotic syndrome in patients with sickle cell disease [53]. Endocapillary and mesangial proliferation with subendothelial deposits of C3 and IgG, suggestive of acute post-infectious glomerulonephritis is frequent on kidney histopathology [54]. Other histological lesions seen on kidney biopsy are shown in Table 14.7. Viral antigens are often present in blood and may be detectable in kidney tissue. Management is supportive; and is often combined with reduction of immunosuppression and administration of intravenous immunoglobulins in transplant recipients with persistent infection [55].

Polyoma Virus

Polyoma virus nephropathy (PVN), caused mainly by the BK virus, occurs in 1–10% of kidney transplants, causing graft loss in about 50% of these cases [56]. PVN is rare in native kidneys of non-kidney organ recipients. Viral replication in the kidney epithelium causes a tubulointerstitial nephritis [57]. The major risk factor for PVN is intense immunosuppression; however, patient, organ, viral and other immunity-related risk factors may play a role. Nephropathy follows viraemia, resulting from latent viruria [58]. PVN often presents as asymptomatic worsening of kidney function, and/or chronic graft dysfunction in the first year of transplantation. The diagnosis of PVN requires urine cytology, urine and plasma BK viral load and kidney biopsy. Viral inclusion bearing epithelial cells called ‘decoy cells’ may be present on urine cytology. Decoy cells ≥10/cytospin [59], a urine BK viral load >10⁷ copies/mL and a plasma BK viral load >10⁴ copies/mL [60, 61] are indicative of a presumptive diagnosis of PVN. Kidney biopsy remains the diagnostic gold standard. Three histological patterns of patchy tubulo-interstitial nephritis with varying degrees of viral cytopathic changes, interstitial inflammation, and in late stages, tubular atrophy and interstitial fibrosis are observed [62]. Three classes of PVN based on tissue replication load, and interstitial fibrosis(ci) score have been described [63]. Reduction of immunosuppression (IS) is the mainstay of management, with addition of antiviral agents in refractory cases. Various algorithms of stepwise and careful reduction of antimetabolites and calcineurin inhibitors are in use. Some antiviral agents, and fluoroquinolones and intravenous immunoglobulins may be useful in refractory PVN. Re-transplantation is possible after graft loss when the viral load becomes undetectable [64, 65].

Cytomegalovirus

Cytomegalovirus (CMV) nephropathy occurs in both immunocompetent and immunocompromised individuals, and results from viral replication in kidney cells and immune complex mediated injury [66]. CMV infection is common after kidney transplantation, where it adversely affects graft and patient survival [67]; however, CMV nephropathy is rare, occurring in <1% of transplanted patients [68]. Kidney disease often occurs during acute systemic CMV illness, following reactivation of latent infection in the setting of intense immunosuppression, or less often during primary infection. The usual clinical manifestation is acute kidney injury with or without haematuria, and varying degrees of proteinuria. Nephrotic syndrome is infrequent. Diagnosis is based on the presence of viral cytopathic changes in kidney tissue, usually in the presence of CMV viraemia. A high viral load of >10,000 copies/mL seems to correlate with CMV nephropathy [69]. Kidney histopathology shows patchy acute or chronic peritubular pleomorphic mononuclear interstitial infiltrates with tubulitis; tubular epithelial cells are markedly enlarged with characteristic intranuclear eosinophilic inclusions (‘owl eye’ type inclusions). Viral particles may be seen in both the nuclei and cytoplasm of infected cells, and CMV is present on immunostaining [70]. Glomerular and vascular lesions may occur either in coexistence with tubulo-interstitial disease or in isolation (Table 14.7). Management of CMV nephritis in kidney allografts involves the use of antiviral agents, reduction of immunosuppression and use of immunomodulators [71] (Table 14.7). CMV nephritis is usually mild and self-limiting in immunocompetent patients.

Varicella Infections

Kidney involvement in varicella zoster virus (VZV) infection is rare and occurs essentially during primary infection in both native and allograft kidneys [72, 73]. Kidney disease is mediated through viral immune complex injury and dysregulation of complement activity [74, 75]. Clinical manifestations include acute glomerulonephritis syndromes, nephrotic syndrome, atypical haemolytic uraemic syndrome, vasculitis and acute kidney injury. Kidney biopsy findings are shown in Table 14.7. Acyclovir, together with supportive care for kidney syndromes is usual care.

Hepatitis E Virus

Kidney disease, essentially glomerulonephritis (GN) is association with acute and chronic hepatitis E virus (HEV) infection in both immunocompetent and immunocompromised individuals [76]. Immune- mediated mechanisms and direct viral cytopathic effects may contribute to kidney damage [77]. A monoclonal gammopathy of renal significance presenting as light chain cast nephropathy was recently reported [78]. Acute kidney failure and the nephrotic syndrome are the usual clinical presentation. In kidney allograft recipients, HEV is associated with proteinuria and a decline in glomerular filtration rate [79]. The spectrum of lesions reported on kidney biopsy are shown in Table 14.7. Treatment is supportive, however in kidney allograft recipients, reduction in immunosuppression and use of ribavirin for 3–6 months are the mainstay of treatment.

Hepatitis A

Hepatitis A virus (HAV)-associated kidney disease occurs in both non-fulminant and fulminant disease, manifesting essentially as AKI with acute tubular necrosis as the main mechanism [80]. Immune-complex-mediated injury, and direct viral cytopathic effects are other suggested mechanisms of kidney pathology [81]. The diagnosis is based on laboratory evidence of infection, in the presence of clinical features consistent with any of the kidney syndromes. Kidney biopsy is rarely required for diagnosis, except with an atypical presentation. Oher mechanisms of AKI and histopathological findings are shown in Table 14.7. Management is supportive and aimed at improving kidney perfusion, and treating complications of kidney syndromes. Kidney recovery is frequent, even in dialysis-requiring AKI.

Hepatitis B Virus

Hepatitis B virus (HBV)-associated nephropathy remains frequent in HBV endemic zones, and occurs mainly with chronic HBV infection. Glomerulonephritis (GN) and polyarteritis nodosa (PAN) from immune-mediated and possible direct viral effects are the main presentations [82]. Consequences of severe liver disease may cause AKI [83]. GN may present with proteinuria, nephrotic syndrome, microscopic haematuria, hypertension or kidney impairment, with the latter unusual in children. HBV DNA, and serological markers of HBV infections are often present in serum, however HBV GN has been reported in HBsAg seronegative patients [84]. Hypocomplementaemia may exist with MPGN and PAN, whereas mixed cryoglobulinaemia is rare. MN, MPGN and MesPGN are the main histological patterns. MN is common in children whereas MesPGN is common in adults and may coexist with MN. Sub-epithelial, sub-endothelial and mesangial deposits of IgG with C3, IgA, IgM and C1q are frequent and immune complexes may contain HBsAg and HBeAg and HBcAg. Other forms of GNs have been reported in adults [85] (Table 14.7). Treatment is with antiviral nucleos(t)tide analogs(NAs). Immunosuppressive agents, pegylated interferon and plasma exchange maybe added to NAs in PAN and rapidly progressive GN [86], as shown in Fig. 14.6. Spontaneous remission is frequent in children with clearance of HBeAg whereas about a third of adults with HBV GN eventually develop chronic kidney failure [85].

Fig. 14.6

Algorithm showing treatment approach to Hepatitis B-associated kidney disease. [BP blood pressure, GFR glomerular filtration rate, HBV Hepatitis B virus, NA Nucleotide/Nucleoside antagonist, ACEi angiotensin converting enzyme inhibitor, Peg-IFN-α pegylated interferon-alfa]

Hepatitis C Virus

Hepatitis C virus (HCV) nephropathy is essentially immune complex mediated GN and vasculitis [87]. The pathological hallmark of HCV-GN is type I MGPN with or without type 2 mixed cryoglobuinaemia [33]. HCV GN presents as an acute nephritic syndrome, varying degrees of albuminuria or rapidly progressive GN, with presence of viral RNA and anti-HCV antibodies in serum. Cryoglobulinaemia occurs in 50–70% and it is associated will low early complement components (C4, C1q, CH50). Kidney histology typically shows MPGN with mononuclear, polymorphonuclear leucocyte infiltrates, and subendothelial deposits of IgG, IgM and C3 [88]. Other glomerular lesions and vascular lesions have been reported (Table 14.7). KDIGO has recommended the use of direct acting antivirals (DAAs) for HCV kidney disease, with the choice, dosage and duration of DAAs therapy based on HCV genotype, glomerular filtration rate, virologic response and possible drug interactions, as shown in Fig. 14.7 [89]. In addition to DAAs, it recommends the use of immunosuppressive agents (IS) with or without plasma exchange in case of a cryoglobulinaemic flare or nephrotic syndrome, with rituximab as first line IS for cryoglobulinaemic kidney disease.

Fig. 14.7

Recommendation grades (1–2) and strength of evidence (a–d) are listed for each recommended treatment regimen and HCV genotype. (a) Recommended Hepatitis C virus (HCV) direct-acting antiviral (DAA) treatment regimens for patients with CKD G1-G5D and kidney transplant recipients (KTRs), by hepatitis C virus (HCV) genotype. (b) Treatment scheme for CKD stages G1-G5D patients with confirmed Hepatitis C infection. (c) Treatment algorithm for Kidney Transplant Recipients with confirmed Hepatitis C infection, by GFR and HCV genotype. CKD chronic kidney disease, DAA direct-acting antiviral, GFR glomerular filtration rate, HCV Hepatitis C virus, NAT nucleic acid testing

HIV

Both acute and chronic kidney disease are common in the course of HIV infection. Mechanisms of kidney injury in the course of HIV infection vary from direct viral cytopathic effects, immune complex disease, and systemic complications of immunodepression and infection or their therapies [90, 91]. The diagnosis of kidney disease in an HIV-positive patient must therefore consider whether patient is combination anti-retroviral therapy (cART)-naïve or not, and whether there is an ongoing co-infection. HIV-associated nephropathy (HIVAN), focal segmental glomerulosclerosis (FSGS) and HIV immune complex disease (HIVICK) are the main kidney manifestations of HIV infection. HIVAN, the most frequent cause of kidney disease in HIV-positive individuals of African descent, results from the cytopathic effects of the virus on visceral and parietal epithelial cells [92]. cART-naïve African blacks with apolipoprotein-1 (APOL-1) G1/G2 variants are especially at risk [93, 94]. The lifetime risk of developing HIVAN in an untreated HIV-positive black patient is 2–10%, but the risk rises to 50% if the patient is homozygous for APOL-I variants [95]. HIVAN typically presents with varying degrees of proteinuria or the nephrotic syndrome with progressive kidney failure. Histologically, classic HIVAN is characterized by collapsing glomerulopathy and attendant tubulointerstitial disease including tubular microcyst formation, interstitial inflammation and tubular injury [91]. HIVICK represents a heterogenous group of proliferative immune-complex mediated GN occurring in a patient with active HIV infection without other possible aetiologies. HIVICK usually manifests as a nephritic or nephrotic-nephritic syndrome in the absence of coinfections such as HBV or HCV. Various proliferative GNs are seen on kidney histology in HIVICK with a post-infectious GN histological pattern observed in about 50% of cases [96]. Other podocytopathies, tubulointerstitial and vascular diseases have been reported in the setting of HIV infection, as shown in Table 14.7. Management involves viral suppression with cART, and measures to slow progression of chronic kidney disease. Recommendations on the screening, management and monitoring of kidney disease in HIV-positive individuals were published recently [91].

Severe Acute Respiratory Syndrome Coronavirus-2 [SARS-CoV-2]

The global pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has affected millions of people around the world, and kidney disease is increasingly recognized as one of its serious complications. A study of 710 hospitalized patients in Wuhan, China with COVID-19 showed that 44% had proteinuria and haematuria, and 26.7% had haematuria on admission. The prevalence of elevated serum creatinine and blood urea nitrogen was 15.5% and 14.1%, respectively. AKI occurred in 5.1% and was associated with a four-fold increase in mortality [97]. A systematic review reported the incidence of AKI to be 8.9% in 6945 COVID-19 patients [98]. There was a higher risk of mortality (RR 3.08–4.19) in severe AKI (AKI Stage 3, or requiring KRT) was reported in a meta-analysis [99]. The proposed mechanisms of kidney injury are diverse, and include direct viral infection, effects on the renin-angiotensin-aldosterone system, haemodynamic instability, coagulopathy and cytokine storm [100]. Histology of native and allograft kidney biopsies in 17 patients in New York, 15 of whom presented with AKI, and 9 with nephrotic range proteinuria, showed that 5/14 native kidneys had collapsing glomerulonephritis (cGN); 2 with membranous GN; one each with minimal change disease, lupus nephritis with crescents, anti-GBM nephritis; and 4 with acute tubular injury (Table 14.7). The 3 allograft biopsies showed acute T-cell mediated rejection, cortical infarction and acute tubular injury. Three patients with cGN (labelled as “COVAN”) and one with minimal change disease were shown to have APOL1 high-risk genotype [101]. In a study of 114 chronic haemodialysis patients from New York, intensive care unit (ICU) admission was required in 13.2% and 16.7% required mechanical ventilation with an overall mortality of 28%; of 86.7% of those requiring ICU, nearly 100% required mechanical ventilation [102].

Kidney transplant recipients appear to be at increased risk of severe COVID-19 disease and mortality rate of 28% was reported in one centre [103]. Treatment is supportive with supplemental oxygen, anticoagulation and dexamethasone for those requiring oxygen, with various agents under clinical trial (including remisidivir, tocilizumab). The vaccines against SARS Cov-2 have reduced the infection rates, severe infection, hospitalization and mortality. Randomised controlled trials to date have shown benefits of dexamethasone, tocilizumab, neutralizing antibodies, and remdesivir.

Protozoal and Parasitic Infections and the Kidney

Malaria

The World Health Organization (WHO) reported 228 million cases of malaria worldwide in 2018, 93% in Africa; 405,000 deaths were reported, 94% of which occurred in Africa [104]. Figure 14.8 shows the distribution of malaria worldwide [106]. The most vulnerable groups are young children, who have not yet developed immunity to malaria, and pregnant women, whose immunity has decreased with pregnancy. Malaria is transmitted by the bite of an infected Anopheles mosquito. There are four pathogenic species of malaria: Plasmodium falciparum, P. vivax, P. ovale, P. malariae; P. falciparum causes the most severe disease with heaviest parasitaemia. The clinical presentation of severe disease is dehydration with hypotension, oliguria, severe anaemia and jaundice.

Fig. 14.8

Countries with indigenous cases in 2000 and their status by 2020: Countries with zero indigenous cases for at least three consecutive years are considered to have eliminated malaria. In 2020, the Islamic Republic of Iran and Malaysia reported zero indigenous cases for the third consecutive year, and Belize and Cabo Verde reported zero indigenous cases for the second time. China and El Salvador were certified malaria free in 2021, following 4 years of zero malaria cases. (Reproduced with permission from the World Health Organisation (WHO) [105])

Kidney Disease with Malaria

Malarial nephropathies are reported in endemic areas, such as Southeast Asia, India, and Sub-Saharan Africa [107,108,109]. Histologic evidence shows the presence of acute tubular necrosis, interstitial nephritis and glomerulonephritis [110,111,112,113] (Table 14.8).

Table 14.8 Kidney disease with different malaria species

Acute kidney injury (AKI) occurs in severe malaria in less than 4.8% of cases, with clinical presentation of hypotension, oliguria, severe anaemia, jaundice, and hepatosplenomegaly and a high risk of mortality (15–45%) [107,108,109]. Risk factors for malarial AKI include delayed diagnosis, heavy parasitaemia, volume depletion, hyperbilirubinaemia, intravascular haemolysis, kidney ischaemia, sepsis, disseminated intravascular coagulation (DIC), cytoadherence to endothelial cells, and microvascular sequestration [114]. Endothelial activation leads to the release of several cytokines, including thromboxane, catecholamines, endothelin and other inflammatory mediators, that are also implicated in the pathogenesis of malaria-associated kidney injury [114].

Immune system activation in malaria involves Th1 and Th2 responses [110]. When the Th2 response prevails (especially with infection by P. malariae), complement activation occurs, with immune complex deposition leading to glomerulonephritis. When Th1 response is predominant, acute interstitial nephritis and acute glomerulonephritis occur. Renal cortical necrosis has also been described in malaria, characterizing more severe kidney injury and is generally associated with non-recovery of kidney function and development of end-stage kidney disease (ESKD) [112]. Hepatic dysfunction also contributes to kidney disease in malaria: hyperbilirubinemia can lead to cast nephropathy, and AKI, and liver disease and its complications can also cause AKI (hepato-renal syndrome (HRS)) [111, 113, 115,116,117]. The principal pathogenic mechanisms of kidney disease in malaria are depicted in Fig. 14.9.

Fig. 14.9

Mechanisms of kidney disease with malaria (adapted from Barsoum RS, 1998) [110]. ATN acute tubular necrosis, TIN tululo-interstitial nephritis, AGN acute glomerulonephritis, PGN progressive glomerulonephritis, CIC circulating immune complexes, RBC red blood cell

Diagnosis

Microscopy is the gold standard and preferred option for diagnosing malaria. In nearly all cases, examination of thick and thin blood films will reveal malaria parasites. Thick films are more sensitive than thin films for detecting low levels of parasitaemia.

Rapid diagnostic tests (RDT) are useful for diagnostic purposes, especially for diagnosing malaria in patients who have recently received antimalarial treatment and in whom blood films are transiently negative for malaria parasites. Commonly targeted antigens are histidine-rich protein 2 (HRP2), which is specific for P. falciparum, and plasmodium lactate dehydrogenase (pLDH), which is present in all Plasmodium species [115, 116].

Treatment

The control and eradication of malaria demands a multifaceted approach, including insecticide spraying and insecticide-treated bed nets.

Close monitoring with rehydration, correction of hypoglycaemia (if present) and control of any seizures are important. If the patient remains oliguric after adequate rehydration, and kidney function continues to decline, then KRT (haemofiltration or haemodialysis, and if neither is available, peritoneal dialysis) should be implemented, especially for severe disease. Haemofiltration is more efficient, and is associated with a significantly lower mortality than peritoneal dialysis. When possible, refer the patient to a dialysis unit.

The current WHO-recommended first-line treatment for the majority of malaria cases is artemisinin-based combination therapy (ACT) (Table 14.9).

Table 14.9 Treatment of severe malaria [117]

Schistosomiasis

Approximately 240 million people worldwide, living in poor communities without potable water and inadequate sanitation, are affected by schistosomiasis, which is prevalent in tropical and sub-tropical areas of the world (Fig. 14.10) [118], with 90% living in Africa. It is estimated that more than 200,000 deaths per year are due to schistosomiasis in sub-Saharan Africa. Table 14.10 depicts the geographical distribution of the different schistosomal species [119].

Fig. 14.10

World-wide Prevalence of Schistosomiasis [118]. (Reproduced with permission from the authors of Ismail et al., 2016 [118])

Table 14.10 Geographical distribution of the different types of Schistosomes [119]

Clinical Features

The incubation period for patients with acute schistosomiasis is usually 2–12 weeks; many people are asymptomatic and have subclinical disease during both acute and chronic stages of infection. Acute infection (Katayama syndrome) may present with rash, fever, headache, myalgia, and respiratory symptoms. Eosinophilia is often present with hepato- and/or splenomegaly [120].

Clinical manifestations of chronic disease result from host immune responses to schistosomal ova. S. mansoni and S. japonicum ova most commonly lodge in the blood vessels of the liver or intestine and can cause diarrhoea, constipation, and blood in the stool. Chronic inflammation can lead to bowel ulceration, hyperplasia, and polyposis; and with heavy infections, may result in liver fibrosis and portal hypertension. S. haematobium ova tend to lodge in the urinary tract causing dysuria and haematuria. Chronic infections may increase the risk of bladder cancer. S. haematobium ova deposition has also been associated with damage to the female genital tract, causing female genital schistosomiasis. Central nervous system lesions are rare and due to ectopic deposition of ova in the spinal cord (S. mansoni or S. haematobium) or brain (S. japonicum) forming granulomas that act as space occupying lesions [121].

Kidney Disease

Glomerular disease occurs in 5–15% of those with S. mansoni infection [122], and has been described in 10–12% of autopsy studies [123]; proteinuria occurs in 20% of S. mansoni-infected patients [124]. Glomerular injury is due to the deposition of schistosomal antigens in the glomerulus and subsequent immune response [121]. The histopathological patterns described are mesangial proliferative GN, membranoproliferative GN, FSGS, proliferative GN and amyloidosis [122].

S. haematobium infections present with haematuria, with granuloma formation; if untreated, the disease may progress to bladder fibrosis, calcification, vesico-ureteric reflux and hydronephrosis, and CKD [120]; the risk of bladder cancer is increased. Rarely, glomerulopathy has been described with S. haematobium, with a case report of membranoproliferative GN [123].

Figure 14.11 describes the timelines associated with the pathogenesis and the different disease manifestations of schistosomiasis [124].

Fig. 14.11

Timelines, Clinical features and Pathogenesis of Schistosomal Disease (adapted from Barsoum R et al., 2013 [124])

Diagnosis

Schistosomiasis is diagnosed by the detection of ova in stool (S. mansoni, S. japonicum, S. mekongi, and S. intercalatum) or urine (S. haematobium) specimens. Antibodies and/or antigens detected in blood or urine samples are also indicative of infection [119, 120].

Treatment

Infections with all major Schistosoma species can be treated with praziquantel (Table 14.11). Although a single course of treatment is usually curative, repeat treatment may be needed after 2 to 4 weeks to increase effectiveness [119].

Table 14.11 Treatment schedule for Schistosomiasis by Schistosoma species infection

Prevention and Control

The control of schistosomiasis is based on large-scale treatment of at-risk population groups, access to safe water, improved sanitation, education, and snail control. Preventive measures include avoiding contact with freshwater in disease-endemic countries.

The WHO strategy for schistosomiasis control focuses on reducing disease by periodic, targeted treatment with praziquantel of all at-risk population groups [119].

Fungal Infections and Kidney Disease

Fungal infections occur more commonly in hospitalized or immunocompromised patients; Table 14.12 outlines the major risk factors for fungal infections of the kidney. Most common organisms are Candida species [125]; less common fungi are filamentous fungi (Mucor, Aspergillus, Penicillium); and rare are endemic fungi (Blastomycosis, Histoplasmosis, Coccidioidomycosis). Patients who are symptomatic usually have urinary tract obstruction from masses of fungal elements (fungal balls). Angio-invasion by fungi may lead to numerous micro-abscesses in the kidney, and extensive kidney infarcts, leading to kidney dysfunction. Treatment with systemic antifungal agents, and surgical removal of the obstructing mass is usually required [126]. In extensive disease, mortality remains very high, especially with angio-invasive fungal infection with mucormycosis and aspergillus infections [127].

Table 14.12 Major risk factors for fungal infections of the kidney

Conclusions

Kidney and urinary tract infections are associated with significant morbidity—and amongst vulnerable groups, mortality. The first clinical case describes a bacterial infection with E. Coli, and illustrates how clinical presentations with urinary tract infection may be unusual, but with appropriate clinical awareness, affected patients can be commenced on appropriate antibiotics early, and hence offered the best chance of a full recovery. The second clinical scenario illustrates the reversible nature of infection-related immune-mediated glomerulonephritis, which may present in a young female who is very unwell, confused and dialysis dependent.

Questions

• 1. A 55 year old man presented to the emergency room with fever, non-productive cough, anosmia, muscle aches and fatigue for one day and sore throat for 3 days. He had been to his local pub 5 days previously. His temperature was 38.3 °C, BP 124/76, respiratory rate 28/min and oxygen saturation 88%. Chest radiograph was suggestive of bilateral lower lobe interstitial pneumonitis. Laboratory results revealed haemoglobin 13.3 g/dL; white cell count 4.1 × 10⁹/L; lymphocyte count 1.3 × 10⁹/L; blood glucose 12.2 mmol/L; serum creatinine 98 μmol/L; CRP 185 mg/L. Three days after admission he was breathless and transferred to ITU, his creatinine increased to 210 μmol/L.

  What is the most likely cause of his illness?

  • A. COVID-19

  • B. Cytomegalovirus infection

  • C. Staphylococcus infection

  • D. Pneumococcus infection

  • E. Malaria

  Answer: A

  A nasal swab PCR confirmed the diagnosis of COVID-19. He was admitted to the intensive care unit and commenced on intravenous fluids, high flow oxygen via a nasal cannula, enoxaparin 20 mg subcutaneously, dexamethasone 6 mg daily intravenously and insulin adjusted according to glucometer readings. He was transferred out of ICU after 5 days and continued to improve in hospital.

• 2. A 30 year old black woman, recipient of a deceased donor kidney transplant 3 months previously, was noted to have a decline in her baseline kidney function at a clinic visit. She had received antithymocyte globulin, high dose steroid induction therapy and was being maintained on tacrolimus, mycophenolate mofetil (MMF) and prednisolone. She had been noted to be CMV IgG positive while on dialysis. Her BP was130/60 mmHg, pulse 78/min and temperature 39 °C. Laboratory tests: haemoglobin 11.8 g/dL; WCC 3.1 × 10⁹/L; platelet count 130,000; serum creatinine 180 μmol/L from a previous baseline of 110 μmol/L. Urine examination revealed 50 red cells/HPF and proteinuria of 0.5 g/day. Tacrolimus levels were between 5 and 15 ng/mL. She underwent a kidney biopsy.

  Histology of the allograft biopsy showed a peritubular mononuclear interstitial infiltrate; some tubular cells had intranuclear inclusions.

  What is the most likely diagnosis?

  • A. Acute cellular rejection

  • B. Acute antibody mediated rejection

  • C. BK virus infection

  • D. Cytomegalovirus infection

  • E. Tacrolimus toxicity

  Answer: D

  CMV viral load was 15,000 copies/mL. She was treated with intravenous ganciclovir 5 mg/kg every 12 h for 14 days, and thereafter maintained on valganciclovir 900 mg daily for 30 days. MMF was discontinued, tacrolimus dose was optimized according to blood levels, and she continued with low dose prednisolone. Her serum creatinine stabilized at 125 μmol/L.

• 3. An 18-year old boy, recipient of a second (deceased donor) kidney transplant was noted to have an asymptomatic rise in his serum creatinine during a routine clinic visit 12 months after transplantation. He had received antithymocyte globulin, high dose steroid induction therapy and was being maintained on tacrolimus, mycophenolate mofetil (MMF) and prednisolone. He had been noted to be CMV IgG positive previously. He was noted to have haemoglobin 12.8 g/dL; WCC 5.1 × 10⁹/L; platelet count 230,000; serum creatinine 220 μmol/L from a previous baseline of 120 μmol/L. Urine cytology showed epithelial cells with viral inclusions ‘decoy cells’, Allograft biopsy showed mononuclear interstitial inflammation, and some degree of tubulitis with basophilic changes of the tubular epithelium.

  What is the most likely diagnosis?

  • A. Acute cellular rejection

  • B. Acute antibody mediated rejection

  • C. BK virus infection

  • D. Cytomegalovirus infection

  • E. Tacrolimus toxicity

  Answer: C

  He had a urine BK load of 11⁷ copies/mL and a serum BK viral load of 10⁵ copies/mL. His MMF dose was halved, and tacrolimus trough levels lowered and he was treated with leflunomide 100 mg daily for 5 days and 40 mg daily thereafter until the virus was cleared. His kidney function gradually stabilized to around his baseline levels and surveillance for BKV is carried out on a monthly basis.

• 4. A 45 year old black man was recently diagnosed with HIV infection and referred to a Renal Clinic with proteinuria and renal dysfunction. He had minimal ankle oedema, BP 126/82 and had 3 g proteinuria/day. His serum albumin was 25 g/L, serum cholesterol 4.1 mmol/L, serum creatinine 188 μmol/L, eGFR 42.1 mL/min/1.73 m², CD4 count 180 cells/mL, viral load 125,000 copies/mL. He underwent a kidney biopsy.

  What is the most likely biopsy diagnosis?

  • A. Crescentic glomerulonephritis

  • B. Focal segmental glomerulonephritis

  • C. Membranous glomerulonephritis

  • D. Membranoproliferative glomerulonephritis

  • E. Minimal change disease

  Answer: B

  His kidney biopsy showed typical HIV associated nephropathy, with glomerular collapse, microcystic tubular dilatation and interstitial inflammation. He was commenced on Losartan 50 mg daily, and Abacavir 300 mg BD, Lamuvidine (3TC) 150 mg daily and Dolutegravir 50 mg daily. Avoid fixed dose combinations if GFR < 50 mL/min, and tenofovir if possible. His APOL1 genotype was not available.

• 5. A 25 year old man was admitted to the emergency room with a fever of 39.1 °C, and dehydration. He had been on a beach vacation in Mozambique 2 weeks previously. He was noted to have tachycardia of 100/min, BP 96/60 and was pale and had a 2 cm splenomegaly. His haemoglobin was 10.1 g/dL; white cell count 4.1 × 10⁹/L; platelets 92,000; serum bilirubin 35 mmol/L; blood urea 32 mmol/L; serum creatinine 220 μmol/L.

  What is the most likely cause of his acute kidney injury?

  • A. Cytomegalovirus infection

  • B. Epstein barr virus infection

  • C. Malaria

  • D. Pneumococcal infection

  • E. Staphylococcus infection

  Answer: C

  A thin smear revealed the presence of tropozoites of P falciparum. He was commenced on intravenous fluids and therapy with artesunate 2.4 mg/kg intravenously immediately and 12 hourly for 24 h and thereafter switched to oral treatment with artemether-lumefantrine for 3 days. A blood smear at 72 h demonstrated that the parasitaemia had been eradicated and he made a a full recovery.

• 6. A 45 year old man, a visitor from Egypt, was hospitalized with abdominal distension. He had been an agricultural worker. He was noted to have hepatosplenomegly. Investigations showed dipstick proteinuria of 3+, and was measured to be 2.9 g/24 h; serum albumin 35 g/L; serum globulins 50 g/L; haemoglobin was 10.8 g/dL; white cell count 4.1 × 10⁹/L; platelets 112,000; serum bilirubin 10 mmol/L; blood urea 5 mmol/L; serum creatinine 88 μmol/L. Ultrasound of the liver was suggestive of hepatic fibrosis, and was confirmed by fibroscan. A kidney biopsy showed membranoproliferative glomerulonephritis.

  What is the cause of the renal disease?

  • A. Cytomegalovirus infection

  • B. Hepatitis B infection

  • C. HIV infection

  • D. Malaria

  • E. Schistosomiasis

  Answer: E

  A stool specimen showed the presence of schistosoma mansoni. He was treated with praziquantel and advised to avoid future schistosomal infection, and to return to his physician for review.

• 7. A 25 year old forest worker in the Democratic Republic of the Congo presented to the Emergency Department with 3 day history of headache, fever, shivering at night, muscle ache and joint pains. The headache was worst behind the eyes and he also mentioned shivering at night. His temperature was 40.0 °C with a BP of 100/60 and regular tachycardia of 120/min. By Day 4 he had developed a maculo-papular rash with patches of purpura. Haemoglobin 13.0 g/dL, WBC 4.0 × 10⁹/L, platelets 80 × 10⁹/L [normal: 150–400]. Creatinine 350 μmol/L with urea 40 mmol/L, eGFR 24 mL/min/1.73 m². There was proteinuria 0.6 g/L and RBC 50–100/μL. Renal biopsy was not considered as it was felt that it would not influence treatment; furthermore it would add an unnecessary hazard for someone already at risk of bleeding.

  What is the most likely diagnosis?

  • A. COVID 19 infection

  • B. Dengue fever

  • C. Ebola virus infection

  • D. Malaria

  • E. Tuberculosis infection

  Answer: B

  He was diagnosed with Dengue fever and managed with supportive treatment and scrupulous attention to clinical signs, pulse, blood pressure and urine output replacing fluid as necessary but avoiding overload. There is unfortunately no specific treatment for dengue virus and as yet no vaccine.

• 8. An 18 year-old female presented with history of fever for 2 weeks, and the passage of brown urine for 6 days, generalized body swelling for 5 days followed by reduced urine output and breathlessness for 2 days. She had a seizure episode a few hours before presentation. She had noted skin infections 3 weeks preceding the above symptoms. On presentation, she had impaired consciousness (GCS 8/15) but recovered within a few hours. She was pale, with bilateral pitting leg oedema temperature of 37.8 °C, respiratory rate 38 breaths/min, pulse 110 bpm and BP 160/110 mmHg. Urinalysis showed blood, protein, and microscopy revealed red cell casts. Her blood tests showed sodium: 122 mmol/L, potassium: 5.6 mmol/L, HCO₃: 12.4 mmol/L, chloride: 84.4, iCa: 1.01, BUN: 63.3 mmol/L, creatinine: 884 μmol/L, haemoglobin: 8.3 g/dL, leukocytosis with neutrophila of 78%.

  What is the most likeley investigation which will help with diagnosis?

  • A. ASO titre

  • B. ANCA

  • C. Hepatitis B serology

  • D. Kidney biopsy

  • E. Serum immunoglobulin

  Answer: A

  Her ESR was 125 mm/hr and qualitative ASO titre: elevated/positive

• 9. An 18 year-old female presented with history of fever for 2 weeks, red-brown coloured urine for 6 days, generalized body swelling for 5 days followed by reduced urine output and breathlessness for 2 days. She had a seizure episode a few hours before presentation. She had noted skin infections 3 weeks preceding the above symptoms. On presentation, she had impaired consciousness (GCS 8/15) but recovered within a few hours. She was pale, with bilateral pitting leg oedema temperature of 37.8 °C, respiratory rate 38 breaths/min, pulse 110 bpm and BP 160/110 mmHg. Urinalysis showed blood, protein, and microscopy revealed red cell casts. Her blood tests showed sodium: 122 mmol/L, potassium: 5.6 mmol/L, HCO₃: 12.4 mmol/L, chloride: 84.4, iCa: 1.01, BUN: 63.3 mmol/L, creatinine: 884 μmol/L, haemoglobin: 8.3 g/dL, leukocytosis with neutrophila of 78%.

  What is the most likely diagnosis?

  • A. Haemolytic uraemic syndrome

  • B. IgA nephritis

  • C. Lupus nephritis

  • D. Post infectious glomerulonephritis

  • E. Polyarteritis nodosa

  Answer: D

  Her ESR was 125 mm/hr and qualitative ASO titre: elevated/positive

• 10. A 42 year old rural drainage engineer, living in Sao Paulo state in southern Brazil, presented to the Dermatology clinic giving a history of intermittent skin rash sometimes associated with a change in pigmentation. He was found to have heavy proteinuria and referred to the nephrologist. In recent months he had been feeling more tired than usual. He had a pale complexion. There was mild oedema of the ankles. Temperature: 36.5 °C, Haemoglobin 100 g/L, sodium 140 mmol/L, Potassium 5.3 mmol/L, bicarbonate 22 mmol/L, creatinine 216 μmol/L, albumin 23 g/L. Urine protein amounted to 10.5 g/24 h. An MSU revealed neither cells nor blood or glucose; the urine was sterile on culture. A repeat of the investigations a week later gave similar results.

  What is the most likely diagnosis?

  • A. Leptospirosis

  • B. Systemic lupus erythematosus

  • C. Nephropathy of tuberculoid leprosy

  • D. Amyloidosis secondary to lepromatous leprosy

  • E. Falciparum malaria

  Answer: D Amyloidosis secondary to lepromatous leprosy

A. Leptospirosis	Incorrect	Lack of fever, and no active urinary sediment
B. Systemic lupus erythematosus	Incorrect	No joint pain, no fever, no significant urinary sediment
C. Nephropathy of tuberculoid leprosy	Incorrect	Nephrotic syndrome not common in the tuberculoid form of leprosy
D. Amyloidosis secondary to lepromatous leprosy with nephrotic syndrome	Correct	Frequency of amyloidosis in leprosy types: lepromatous [36%], tuberculoid and borderline [5%]. The nephrotic syndrome is a consequence of the amyloidosis.
E. Falciparum malaria	Incorrect	No fever or other evidence of malaria

Test your learning and check your understanding of this book’s contents: use the “Springer Nature Flashcards” app to access questions using https://sn.pub/cz9Cok. To use the app, please follow the instructions in Chap. 1.