Syphilis is a sexually transmitted disease caused by a spirochete Treponema pallidum whose only natural hosts are humans [46]. Renal involvement is rare [47] and is due to direct tissue invasion by the spirochete or is precipitated by immune-mediated mechanisms. The overall seroprevalence is extremely low [48], but syphilis is undergoing resurgence over the last 2 decades in the developed world and the diagnosis can be missed if not suspected clinically [46]. The clinical presentation of syphilis varies widely and depends on the stage of disease. Primary syphilis presents as a painless ulcerated skin lesion (chancre) 2–6 weeks after infection. If untreated, 25% of patients progress to secondary syphilis in weeks to months. It is represented by non-itchy generalized rash, lymphadenopathy, fever, and malaise due to disseminated spirochetal infection. Approximately, 20–40% of untreated secondary syphilis cases progress to tertiary syphilis over 1–30 years after the primary infection. Tertiary syphilis primarily affects the cardiovascular system and brain, and the formation of gumma, i.e., granulomatous locally destructive lesion, is common. Glomerulonephritis related to syphilis occurs during (a) secondary or tertiary syphilis stage, (b) congenital syphilis infection, or rarely (c) after initiation of anti-syphilis therapy [49–52] (Table 3.2). Congenital syphilis due to transmission of organisms from mother to baby during pregnancy or at birth is relatively rare in the Western countries, but membranous nephropathy in an infant should prompt a search for treponemal infection [53].

Proteinuria is the most common renal manifestation and occurs in up to 8% of secondary syphilis patients [49]. It can range from mild proteinuria to nephrotic syndrome in the setting of membranous nephropathy. Mild hematuria, acute nephritis syndrome, renal insufficiency, or rapidly progressive renal failure can all occur depending on the type of glomerulonephritis [54]. Hypocomplementemia is reported with proliferative glomerulonephritis. The most common glomerulonephritis associated with syphilis is membranous nephropathy with variable mesangial hypercellularity. Other patterns reported include proliferative glomerulonephritis (ranging from mild to diffuse ± neutrophils), crescentic glomerulonephritis, and minimal change disease [49, 54]. The immune-mediated glomerulonephritis has immunofluorescence evidence of immunoglobulin and complement deposits. Tubulointerstitial inflammation is often present and tends to be plasma-cell rich. Demonstration of tissue spirochetes indicates direct tissue invasion. Although not specific, positive rapid plasma regain (RPR) or VRDL should raise concern for syphilis. Once suspected, a diagnosis of syphilis can be confirmed by treponemal antibody tests (T. pallidum hemagglutination assay and fluorescent treponemal absorption test). The organisms can also be detected in the tissue by Warthin–Starry silver stain, dark field microscopy, immunofluorescence microscopy, or polymerase chain reaction.

The glomerulonephritis is likely due to the glomerular deposition of treponemal antigen with subsequent binding of the circulating antitreponemal IgG antibody or deposition of circulating immune complexes. Antibodies have been eluted from the kidney biopsy and the treponemal antigen has been demonstrated in the immune deposits in both acquired and congenital syphilis-associated glomerulonephritis [22, 55, 56]. Treponemal antigen–antibody complexes deposited in the glomeruli activate the classical and alternate complement pathway.

Syphilis is treated with penicillin or ceftriaxone and requires 3–6 weeks of therapy. The resolution of glomerulonephritis can take 1–6 months after therapy. The consequent treponemal death triggers a massive release of bacterial antigens and endotoxins causing a systemic reaction referred to as Jarisch–Herxheimer reaction. It usually last only a few hours during which the patient develops fever, chills, tachycardia, flushing, and myalgias. Prominent skin rash can also occur and is thought to be due to immune complex formation and deposition. Rare case reports of renal involvement with transient nephrotic syndrome are also reported [52].

Lyme disease is the most common tick-borne infection in USA, seen especially in the Northeastern regions and Wisconsin [57]. It is a multisystem disorder caused by a spirochete Borrelia burgdorferi and transmitted by ticks of genus Ixodes. Renal involvement is rare and the diagnosis requires high index of clinical suspicion [57, 58]. The early symptoms of fever, fatigue, and the characteristic skin rash of erythema migrans might be forgotten by the patient at presentation. If left untreated, Lyme disease has frequent relapses and remissions manifested by arthritis, cardiac, and neurological symptoms. The diagnosis rests on serological confirmation including ELISA detection of IgM and IgG antibodies specific to B. burgdorferi, western blot, and polymerase chain reaction detection of B. burgdorferi DNA in body fluids [59–61]. Unfortunately, all these tests are prone to false-positive and false-negative results, further complicating the diagnosis.

The renal symptoms are microscopic hematuria and proteinuria, but nephrotic syndrome is not uncommon and rare cases present with acute renal failure [58, 62, 63]. Although hypocomplementemia is helpful when present, C3 levels are often normal. Membranoproliferative glomerulonephritis is the most common histology on renal biopsy, but mesangioproliferative glomerulonephritis, membranous nephropathy, and IgA nephropathy have also been described [58, 61, 62] (Fig. 3.3). Mild interstitial inflammation accompanies the glomerular changes and the extent of chronic tubulointerstitial damage is variable. Interstitial foam cells have been described with chronic nephrotic range proteinuria. IgG and dominant C3 staining in the mesangium and capillary walls is typical and on rare occasion IgA staining has been described in mesangioproliferative glomerulonephritis [58, 62]. The electron-dense deposits are mostly in the mesangium and subendothelium with rare subepithelial deposits.

Lyme disease associated with glomerulonephritis is caused by chronic antigenemia, robust host response with antibody production, and immune complex formation. The circulating immune complexes deposit in the glomeruli and initiate tissue injury [57]. There may be a role for autoimmunity as B. burgdorferi antigens mimic self-antigens at the molecular level [64]. The treatment of Lyme disease includes oral doxycycline for 14–28 days or even longer in chronic infection [65]. The renal disease of membranous glomerulonephritis may respond to steroids, intravenous immunoglobulin, and on occasion, plasmapheresis [61]. Although not universal, complete resolution of membranoproliferative glomerulonephritis has been described in the literature [61].

Bartonella species are fastidious gram-negative organisms; B. henselae and B. quintana are associated with human disease. B. Henselae is the culprit in ‘cat scratch’ disease; organisms are carried by fleas, transmitted to cats, and then to humans through broken skin, most typically via scratch from a kitten [66]. In immunocompetent individuals, there is a self-limited regional lymphadenitis, but in immunosuppressed patients more widespread granulomatous inflammation can involve spleen, liver, central nervous system, and bone, and in severely immunocompromised patients angiomatosis (bacillary angiomatosis of the skin or peliosis of the liver–spleen) occurs [66, 67]. Patients with cardiac or valvular defects are at risk for Bartonella endocarditis, with Bartonella comprising up to 17% of endocarditis, and 28% of ‘culture negative’ endocarditis [66, 67]. Since Bartonella endocarditis is often blood ‘culture negative,’ it requires a high index of suspicion in conjunction with serologic or PCR studies for confirmation [68]. However, Bartonella serologic testing is not particularly specific, though very high titers have increased specificity (>1:800) [67, 68]. Cases of Bartonella-associated glomerulonephritis have been reported; one series cited “kidney failure” in 45% of patients with Bartonella endocarditis [68]. Importantly, in some cases the renal biopsy findings have prompted the rigorous search for an infectious process [68, 69].

As with other types of infection-associated glomerulonephritis, histopathologic findings in Bartonella-related glomerulonephritis have been variable. Light microscopy generally shows a proliferative and/or focal necrotizing-crescentic glomerulonephritis [66–72]. Immunofluorescence results are also variable, and have most commonly been reported as IgM-dominant or pauci-immune, but cases of ‘full house’ deposition, C3-dominant, or IgA-dominant staining have been documented [66–72]. Ultrastructural studies tend to show mesangial electron-dense deposits, most often without the classic subepithelial ‘hump’ deposits [66–72]. Thus, infection should be considered in glomerulonephritis with an IgM-dominant immunofluorescence pattern. Further, a Bartonella and other endocarditis-associated glomerulonephritides often are associated with positive ANCA serologies. Thus, an infectious process should remain on the differential in cases of ANCA-positive necrotizing and crescentic glomerulonephritis [66, 71, 73] (Fig. 3.2).

Brucellosis is a zoonotic infection caused by gram-negative coccobacilli Brucella sp., and is endemic in Middle East and Mediterranean countries. Close contact with infected animals, consumption of unpasteurized dairy products, and inhalation of aerosols leads to human infection [74]. All organ systems are affected and clinical picture can be varied. Although Brucella organisms can be isolated in 4–5% of infected patients, renal involvement is rare [75]. The renal histology in Brucella infection can be in the form of acute interstitial nephritis (due to direct invasion of bacterium), chronic granulomatous inflammation, renal abscess, and occasionally glomerulonephritis.

Derived from the limited literature related to Brucella glomerulonephritis, most patients present with hematuria, proteinuria (can be nephrotic range), and sometimes renal insufficiency. Low C3 levels can be seen, especially with membranoproliferative glomerulonephritis. The site of infection can vary, but glomerulonephritis has been reported with endocarditis, mycotic aneurysm, and others [74, 76]. Although the data is limited, the most common Brucella organism isolated is B. melitensis. The renal biopsy findings reported are membranoproliferative glomerulonephritis, mesangioproliferative glomerulonephritis, cryoglobulinemic glomerulonephritis, diffuse proliferative v, IgA nephropathy, and membranous nephropathy [76–81]. Definitive diagnosis rests on serological confirmation (serum agglutination test, ELISA) or isolating brucellae from blood or infected tissues. Polymearase chain reaction results in rapid confirmation of the infectious organism and is preferred over cultures [82]. Circulating immune complexes with glomerular deposition is the main mechanism involved, likely initiated by chronic antigenemia [83]. On occasion, proliferative and crescentic glomerulonephritis or renal vasculitis occurs in the absence of immune complexes [76]. It has been suggested that endotoxemia triggers a cellular inflammatory response within the glomerulus with subsequent injury in the absence of immune complexes as in ANCA-mediated injury [76]. Treatment of Brucella infection-related glomerulonephritis includes doxycycline in combination with rifampin, gentamicin, streptomycin, or trimethoprim/sulfamethoxazole. Additional steroid therapy may be helpful in the setting of crescentic glomerulonephritis and vasculitis [76].

Mycobacterium tuberculosis complex: The mycobacterial infections in humans include tuberculosis caused by members of Mycobacterium tuberculosis complex, mainly M. tuberculosis and rarely by a bovine tubercle bacillus, M. bovis [84]. Both are obligate pathogens while most other species within the genus mycobacterium are environmental saprophytes typically not associated with human disease in an immunocompetent state. On occasion, an environmental mycobacterium such as M. avium causes disseminated disease in an immunocompromised human host [85]. The kidney is mainly involved by M. tuberculosis in the form of genitourinary tuberculosis, while M. avium can infect the kidney as part of disseminated disease. Another mycobacterium, M. leprae, is known to affect the kidney in endemic areas [86].

Tuberculosis is caused by either reactivated latent M. tuberculosis infection in an immunosuppressed host or by dissemination of active pulmonary infection. Renal involvement in the form of genitourinary tuberculosis accounts for 14–41% of extrapulmonary tuberculosis in developed countries [84, 87]. The infected pelvic calyces and medulla undergo ulceration and destruction with accumulation of cheesy caseous material [84, 88]. Chronic tubulointerstitial nephritis with necrotizing caseating granulomas is not uncommon.

On rare occasion, M. tuberculosis infection can result in glomerulonephritis, especially in endemic areas [89]. The clinical manifestations of patients with tuberculosis-related glomerulonephritis include hematuria and proteinuria. The systemic symptoms related to tuberculosis infection such as fatigue, mild fever, night sweats, weight loss, and hypertension are more common than local genitourinary symptoms such as urinary frequency, urgency, and flank pain. Accurate diagnosis depends on confirmation of active tuberculosis infection by demonstration of acid-fast bacilli (sputum), cultures (sputum, urine), polymerase chain reaction (renal biopsy tissue), or more recently Quantiferon test [84, 89, 90]. In one study, more than 70% of patients with tuberculosis-related glomerulonephritis had pulmonary or extrapulmonary tuberculosis [89]. Most patients with glomerulonephritis are over 40 years of age, likely reflective of prolonged tuberculosis infection predisposing to the development of glomerular disease. Over 72% of patients with tuberculosis-related glomerulonephritis had IgA nephropathy, but other glomerulonephritides have also been reported. These include mesangioproliferative glomerulonephritis, crescentic glomerulonephritis, collapsing glomerulopathy, membranous nephropathy, and membranoproliferative glomerulonephritis [91–96].

While the immune responses in M. tuberculosis are primarily cell-mediated, there is a humoral component as well [97–99]. High levels of immune complexes have been detected in patients with disseminated tuberculosis [100]. T cell suppressed environment with negative Mantoux skin test while not a requisite may predispose to development of circulating immune complexes [91, 99]. It appears that IgA antibodies directed against A-60 mycobacterial antigen play a role in the frequent association between tuberculosis infection and IgA nephropathy. These antibodies have been detected in the serum of patients with active tuberculosis as well as the immune complexes of IgA antibodies and mycobacterial antigens [97].

The diagnosis of tuberculosis-related glomerulonephritis is difficult due to nonspecific symptoms and insidious nature of the disease. High index of suspicion is needed. Treatment is mainly antituberculosis therapy and care should be taken to address multidrug-resistant tuberculosis [84]. Resolution of hematuria and proteinuria with treatment also supports the diagnosis of tuberculous glomerulonephritis [89, 99]. Interestingly, rifampin antituberculous therapy in turn can precipitate crescentic glomerulonephritis [101].

Mycobacterium leprae is a weak intracellular acid-fast bacillus that causes either tuberculoid leprosy or lepromatous leprosy base on robustness of the host response. The bacillus has a predilection for Schwann cells and skin. Leprosy is endemic in several developing countries. Although highly infectious with prolonged exposure, clinical disease is less common as M. leprae is slow growing with an incubation period of 2–12 years.

Tuberculoid leprosy is characterized by granulomatous inflammation and paucity of bacilli due to effective cell-mediated immunity. On the other hand, lepromatous leprosy is more common with multibacillary forms associated with weak host defenses. The renal lesions described include glomerulonephritis, granulomatous interstitial nephritis, AA amyloidosis, and pyelonephritis [102].

Glomerulonephritis represents the most frequent type of renal involvement in leprosy, found in approximately 30% of patients [103]. Lepromatous leprosy patients with abundant bacilli are particularly vulnerable. These bacilli trigger a robust humoral response, but these antibodies are not protective against the lepra bacilli. Immune complexes form in this high antibody milieu and glomerulonephritis may ensue. Antigens from other co-infections may also play a role. Skin erythema nodosum has similar pathogenesis and according to one study, there is a strong correlation between erythema nodosum and development of glomerulonephritis [104]. The potential mechanisms for glomerulonephritis and erythema nodosum include either deposition of circulating immune complexes or in situ deposition of lepra antigens. Circulating cryoglobulins have also been documented in leprosy [105]. Lepra bacilli antigens are released in massive amounts after the antibiotic therapy, and immune complexes can be formed in this setting as well [104].

Renal presentation of mild hematuria and proteinuria is common with leprosy-associated glomerulonephritis, but nephrotic syndrome also can occur, depending upon the type of tissue injury [86, 103, 106]. A few patients also have functional tubular defects of acidification or urinary concentration. Histologically, the glomerular changes reported include membranous nephropathy, IgA nephropathy, mesangioproliferative, endocapillary proliferative, or membranoproliferative glomerulonephritis [102, 103, 107]. Crescents are rare and can result in acute renal failure [108]. The tubulointerstitium may show granulomatous inflammation with acid-fast bacilli demonstrated on Fite stain. Immunofluorescence reveals granular C3 and IgG deposits in the mesangium and along the capillary walls. The corresponding electron-dense deposits are in the mesangium and subendothelium. Antibiotic treatment of M. leprae with dapsone, rifampin, and clofazimine is main course of treatment. But steroids and nonsteroidal anti-inflammatory drugs might be of help in the setting of glomerulonephritis related to acute immunological episodes.

Others: There are many other bacterial infections reported in association with glomerulonephritis [44]. Patients with Klebsiella and Mycoplasma pneumonia develop proliferative glomerulonephritis [109, 110]. The renal presentation includes hematuria, proteinuria, or renal insufficiency, but glomerulonephritis may also be clinically occult. Klebsiella polysaccharide antigen has been demonstrated in the mesangial and glomerular capillary wall deposits and the eluate of the glomerulus-bound IgG antibody was specific to Klebsiella [109]. Similar evidence of mycoplasma antigen was found in a patient with Mycoplasma infection-associated diffuse proliferative glomerulonephritis [111]. The serum complement levels are reportedly low in Mycoplasma-associated proliferative glomerulonephritis and the immune deposits are predominantly in the mesangium [110, 111]. Recent reports of Mycoplasma-related crescentic glomerulonephritis and vasculitis have also been documented [112–114]. Following an infection with Mycoplasma, a patient developed MPO-ANCA with subsequent pulmonary-renal syndrome and glomerular crescents [114].

Renal involvement in Salmonella infections is reported to occur in 2–3% of patients, and it includes cystitis, pyelitis, pyelonephritis, and rarely glomerulonephritis [115]. However, it has been postulated that subclinical glomerulonephritis is not uncommon and kidney biopsies performed in three typhoid fever patients with no evidence of renal dysfunction did demonstrate immune complex glomerulonephritis [116]. Reported histological findings in typhoid glomerulonephritis include diffuse proliferation and IgA nephropathy, in addition to thrombotic microangiopathy [117–119]. Deposition of immunoglobulin and C3 is seen along with subepithelial humps on electron microscopy. Salmonella Vi antigen has been demonstrated in the glomerular capillary wall confirming the pathogenic role of Salmonella typhi [116].

Amyloidosis as a complication of chronic inflammatory conditions including infection and autoimmune disease has been recognized for nearly a century [120]. Serum amyloid A (SAA), an acute phase reactant synthesized in the liver in response to IL-1, IL-6, and tumor necrosis factor [121], is the amyloid fibril constituent in this setting, as well as in Familial Mediterranean fever. In the developed world, the incidence of infection-associated SAA amyloid has decreased with reduction in chronic tuberculosis, leprosy, osteomyelitis, chronic decubitus ulcers in paraplegics, and infections in burn patients, hidradenitis suppurativa, dermatoses, and cystic fibrosis [120, 122–124]. However, some of these conditions remain prevalent in less-developed areas of the world [122]. Further, there was an ‘epidemic’ of SAA amyloid amongst illicit drug users with skin infections in the 1970s–1980s, and such cases have been seen continually since then, although infrequently reported [121–123, 125–133].

Menchel et al. and then Neugarten et al. characterized SAA amyloid amongst drug users in New York City. In a group of 150 drug addicts at autopsy, amyloid was identified in 6 of 44 (14%) subcutaneous drug users but in only 1 of 105 (1%) intravenous drug users. Of 23 drug addicts with skin infections, 6 had amyloid (26%) [131, 133]. In a subsequent study incorporating these autopsy cases as well as larger group of biopsy cases, Neugarten et al. identified cutaneous suppurative lesions in 17/20 drug addicts with amyloid [131, 133]. The authors estimated that 25–50% of drug addicts biopsied for proteinuria had SAA amyloid in this era [126, 133]. Other glomerular findings in heroin addicts include focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, or infection-related proliferative glomerulonephritis (endocarditis, skin infection, other) [126, 128].

Patients with infection-associated SAA amyloid present with heavy proteinuria (range 1.5–29 gm/day) [126, 133]. They may have the full nephrotic syndrome, and generally also have elevated serum creatinine, with several reporting polyuria and polydipsia [126, 133]. Patients inevitably had a long history of intravenous drug use, and a more recent history (2–3 years) of cutaneous drug use, so-called ‘skin-popping,’ after veins are longer useable for injection [126, 133, 134]. In a series of renal biopsies from 35 heroin addicts, Dubrow et al. reported older age, longer duration of addiction, lower serum albumin, and lower blood pressure in those with renal amyloid as compared to those with focal segmental glomerulosclerosis [126]. In a contemporary study, skin infections in drug users were frequently polymicrobial, including both methicillin-sensitive and methicillin-resistant Staph. species, Strep. species, and a mixture of anaerobic organisms [135].

Histopathologically, features of SAA amyloid in the kidney are similar to other forms of amyloid. Amyloid deposits in glomeruli are seen in the mesangium and, with extensive deposition, involve and efface much of the glomerular tuft [136] (Fig. 3.4a). Unfortunately, skin infection-associated SAA is often biopsied at this late phase with extensive renal damage. Amyloid deposits are lightly eosinophilic and ‘waxy’ on H&E, pale on PAS, metachromatic (blue-purple) on trichrome, and silver negative [136]. Amyloid ‘spicules’ by light microscopy may be aligned perpendicular to the glomerular basement membrane. SAA amyloid frequently involves the interstitium as well as arteries and arterioles. Congo red staining is positive in amyloid with green birefringence on polarization (Fig. 3.4b). Fluorescent light may also be used to evaluate Congo red or thioflavin stains [136, 137]. By immunofluorescence microscopy, the amyloid deposits are essentially negative for immunoglobulin, light chain, and complement staining, but there is often nonspecific background in the amyloid. Serum amyloid A staining will be positive by immunofluorescence or immunohistochemical methods (Fig. 3.4c); alternatively, mass spectroscopy or other proteomic methods can be used to type the amyloid [138]. Electron microscopy shows deposits with the characteristic randomly oriented fibrils of 8–12 nm diameter [136] (Fig. 3.4d).