The presence of a glomerular disease, is usually suspected from history, physical examination, and specific findings in the urine, in particular hematuria and proteinuria. Together with renal function tests two types of glomerular diseases can be distinguished—nephritic or nephrotic syndrome. Nephritic syndrome is characterized by hematuria and variable degree of proteinuria and renal failure. Nephrotic syndrome includes nephrotic range proteinuria (> 3.5 g/day), decreased serum albumin levels, peripheral edema, and dyslipidemia. Although the two syndromes are discussed as separate entities, overlap between the two is commonly encountered. For example, diabetic nephropathy presents most often as nephrotic syndrome, but some patients also have hematuria. Likewise, many patients with glomerulonephritis also have nephrotic range proteinuria or nephrotic syndrome. Nevertheless, these findings are distinct from those associated with tubulointerstitial disease and renovascular disease.
GN is characterized by inflammatory or vasculitic lesions in the glomerulus. If those lesions affect less than 50% of glomeruli on light microscopy it is called focal, otherwise it is referred to as diffuse GN. If less than 50% of the glomerular tuft is affected it is called segmental. In general, focal GN has a less severe presentation and often a better prognosis. Nephrotic syndrome and/or a significantly reduced glomerular filtration rate are more often seen with diffuse disease.
Most glomerular diseases in older adults are caused by chronic systemic diseases, including arterial hypertension, diabetes, and atherosclerotic vascular diseases and do not present with nephritis or nephrotic syndrome. Furthermore, the incidence and prevalence of GN is likely underestimated in the older adult population since the mainstay of the diagnosis is pathologic evaluation of kidney tissue requiring an invasive biopsy. However, some GNs—notably small-vessel vasculitis, and postinfectious glomerulonephritis (PIGN)—have a second peak in the geriatric population and need to be considered in the differential diagnosis.
GN can be classified into groups based on course, histopathologic findings, and disease etiology. RPGN can be associated with autoimmune processes, infectious diseases, and systemic diseases, in particular vasculitides, malignancies, and medications (Table 87-3). The most common primary GN worldwide is immunoglobulin A (IgA) nephropathy. It can have a highly variable course with some patients presenting with RPGN, approximately 30% to 40% of patients progressing to ESRD within 20 years and other patients only having persistent hematuria without proteinuria and changes in GFR. The incidence of ESRD in the older patients’ IgA nephropathy (over the age of 50) is almost two times higher than that in younger patients. PIGN is considered primarily a childhood disease, but more recently its occurrence in older patients is becoming recognized. PIGN presents typically with hematuria and proteinuria 10 to 14 days after an infection. AKI may or may not be observed. A recent report of 109 cases of PIGN in patients greater than or equal to 65 years diagnosed by renal biopsy showed that 61% of patients had an immunocompromised background, most commonly diabetes or malignancy. Importantly, the most common site of infection was skin, followed by pneumonia and urinary tract infection—all infections that are very common in older adults. The most common causative agent was Staphylococcus (46%) followed by Streptococcus (16%) and unusual gram-negative organisms. Hypocomplementemia was present in more than 70% and almost half of patients required acute dialysis. Only about 20% achieved complete recovery, half had persistent renal dysfunction, and about 30% progressed to ESRD. The factors that increase the risk for ESRD include presence of diabetes, higher creatinine at biopsy, dialysis at presentation, the presence of diabetic glomerulosclerosis, significant tubular atrophy, and interstitial fibrosis on biopsy. In summary, the epidemiology of PIGN is shifting as the population ages. Older men and patients with diabetes or malignancy are particularly at risk, and the sites of infection and causative organisms differ from the typical childhood disease. Prognosis for these older patients is often poor.
TABLE 87-3CLASSIFICATION OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS |Favorite Table|Download (.pdf) TABLE 87-3 CLASSIFICATION OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
|Primary diffuse crescentic glomerulonephritis |
| Type I: anti–GBM-mediated disease without pulmonary hemorrhage (with anti-GBM) |
| Type II: immune complex–associated disease (without anti-GMB or ANCA) |
| Type III: pauci-immune (with ANCA) |
| Type IV: mixed pattern (with anti-GBM and ANCA) |
| Type V: pauci-immune (without ANCA or anti-GBM) |
| Fibrillary and immunotactoid glomerulonephritis |
| Focal sclerosis (rare) |
| IgA nephropathy |
| Mesangiocapillary glomerulonephritis (especially type II) |
| Membranous glomerulonephritis (with or without anti-GBM) |
| Superimposed on another primary glomerular disease |
|Associated with infectious disease |
| Hepatitis B and C |
| Histoplasmosis |
| Infective endocarditis |
| Influenza (?) |
| Mycoplasma infection |
| Poststreptococcal glomerulonephritis |
| Visceral abscesses |
|Associated with multisystem disease |
| Carcinoma (lung, bladder, prostate) |
| Goodpasture disease (anti-GBM with pulmonary hemorrhage) |
| Lymphoma |
| Mixed (IgG/IgM) cryoimmunoglobulinemia (hepatitis C) |
| Relapsing polychondritis |
| Henoch-Schönlein purpura |
| Systemic lupus erythematosus |
| Systemic polyangiitis |
| Churg-Strauss syndrome |
| Microscopic polyangiitis (with ANCA) |
| Wegener granulomatosis (with ANCA) |
| Other variants |
|Associated with medications |
| Allopurinol |
| Bucillamine |
| D-Penicillamine |
| Hydralazine |
| Rifampin |
Small-vessel vasculitis is rare and often presents with systemic symptoms, including fatigue, malaise, loss of appetite, fever, and weight loss. Occasionally hemoptysis, rash, and joint pain are noted. Some patients do not have any systemic symptoms, but rather develop hematuria, variable degree of proteinuria, and rising creatinine. In those patients, a kidney biopsy may show pauci-immune GN.
Complex age-related changes and increased number of comorbidities and sensitivity to drug toxicity can render the diagnosis as challenging. The presence of glomerular disease is usually suspected by history, physical examination, and the presence of abnormal urinary findings—proteinuria (in particular if > 3 g/day), hematuria (in particular if dysmorphic erythrocytes are present), and red cell casts. On the other hand, many patients with GN do not exhibit these specific signs and symptoms but rather present with nephrotic syndrome or CKD and are diagnosed with GN only after a biopsy is performed. Furthermore, proteinuria (usually < 2.5 g/day) and hematuria (without dysmorphic erythrocytes) are commonly seen in patients without glomerular disease. Proteinuria can be due to tubulointerstitial disease and hematuria can be due to extrarenal sources, and is therefore difficult to diagnose, particularly in older adults.
Often patients with GN report constitutional symptoms, including decreased energy, general malaise, decreased appetite, fever and weight loss, and muscle aches. These symptoms are nonspecific and some patients attribute those symptoms to viral infections like upper respiratory infections (URIs). More specific symptoms include new onset of skin rash, joint pain and swelling in metacarpophalangeal joints (MCP) and proximal interphalangeal (PIP) joints, and/or pleuritic or cardiac chest pain secondary to serositis. Shortness of breath, cough, and hemoptysis seen in pulmonary renal syndromes represent an emergency. Any of those symptoms should prompt examination of kidney function and urine. The presence of hematuria and proteinuria should immediately raise concern for GN. Based on serum creatinine levels GN can be classified into acute or rapid progressive GN presenting with acutely rising creatinine, and chronic GN with stable and normal or slowly rising creatinine. RPGN constitutes an emergency as renal failure can develop within days unless appropriate treatment is initiated.
The evaluation of a patient with suspected glomerular disease depends primarily on the acuity of the presentation. If the patient presents with acute renal failure (ARF) and has hematuria and proteinuria, RPGN has to be suspected. This constitutes emergent further diagnostic testing which includes evaluation of urine sediment for dysmorphic erythrocytes and cellular (red cell) casts, quantification of C3 and C4 to determine complement activation and consumption, complete blood counts with differential to detect anemia, thrombocytopenia, leukocytosis, and testing of hemolysis (lactate dehydrogenase [LDH], haptoglobin), coagulation, and liver function. An ultrasound of the kidneys will determine the presence of nephrolithiasis, obstructive nephropathy, reflux nephropathy, nephrocalcinosis, cystic kidney diseases, and other conditions. Furthermore, small kidneys with increased echogenicity on ultrasound may suggest long-standing disease. Serologic evaluation includes markers for viral infections, in particular hepatitis B and C and HIV, and paraproteinemia (serum and urine protein electrophoresis, immunofixation for light chains). Testing for markers for autoimmune diseases should be considered in patients presenting with constitutional symptoms such as fever, chills, malaise, loss of energy, unexplained weight loss, and/or new onset of joint pain (in particular in small joints), skin rash, or pulmonary symptoms (cough, hemoptysis, or shortness of breath). A thorough physical examination is critical to detect signs of systemic diseases, including skin rash, Ehlers-Danlos spots suggestive of endocarditis, lower extremity edema, joint swelling or warmth, and wheezing or rales.
The decision whether and when to perform a kidney biopsy depends on the overall condition and status of each individual patient. Increased frailty and decreased functional status at baseline, preexisting baseline CKD with decreased eGFR and small echogenic kidneys on ultrasound, limited life expectancy as well as anemia, thrombocytopenia, and coagulopathy increase the risk for complications after kidney biopsy.
If the patient has stable renal function but a glomerular disease is suspected because of hematuria and proteinuria the patient should first undergo serologic evaluation. Depending on those results a kidney biopsy can be considered. If the creatinine is rising and pre- and postrenal causes of AKI have been excluded, an urgent kidney biopsy may be considered.
The diagnosis of RPGN may justify empiric immunosuppressive therapy. Even with stable kidney function it is important to establish specific-disease etiologies to guide therapy.
Corticosteroids are the mainstay in the treatment of acute and chronic GN. If an acute GN is suspected and either creatinine is rising or systemic potentially life-threatening symptoms are present pulse-dose corticosteroids (1 g methylprednisolone IV once daily × 3) followed by oral prednisone, usually 1 mg/kg body weight (up to 60 mg) once daily for up to 2 to 3 month followed by a slow taper over another 2 to 3 months is often used. Patients need to be monitored closely for any signs or symptoms of recurrence of disease in particular during tapering prednisone dose and after stopping it.
Cytotoxic therapy with agents such as cytoxan is considered in patients with crescentic and proliferative GN detected on biopsy or in the setting of other potentially life-threatening complications (ie, hemoptysis, severe hemolytic anemia, and thrombocytopenia). Whether to use IV or oral cytoxan and length of therapy depends on the specific disease, severity of initial presentation, and degree of response. Anti-CD20 antibodies (rituximab) can be considered with equivalent potency compared to cytoxan as suggested by recent studies.
Maintenance therapy is usually required to prevent disease recurrence. To minimize the dose of corticosteroids commonly used drugs include azathioprine (Imuran) or mycophenolate mofetil. The goal is to maintain the patient on the lowest dose of corticosteroids and steroid-sparing agents without flare of the disease or significant complications of therapy. Monitoring usually includes renal function, proteinuria, blood counts, liver function tests, and signs or symptoms of original disease or infections.
Supportive care is critical for patients with GN, in particular management of blood pressure (hyper- and hypotension), intravascular and total body fluid volume (hypervolemia with peripheral and pulmonary edema requires use of diuretics; hypovolemia requires isotonic fluid), electrolyte abnormalities. and unwanted effects and complications of therapy.
Dietary restrictions include low-salt diet if patient has edema, hypertension, or nephrotic syndrome. High-protein diet should be avoided like in any patient with proteinuria, but low-protein diet has not been shown to benefit.
Prevention of recurrence, flares, and complications of therapy remains a life-long aspect of care, even if patient has been tapered off immunosuppressive medication. Strategies to prevent long-term complications of corticosteroids like osteoporosis, obesity, and type 2 diabetes should be implemented at the beginning of therapy.
Treatment of GN is associated with significant side effects and complications, which need to be balanced with side effects and complications of renal failure and ESRD. It is important to discuss the risks and benefits of all options with specific consideration of the underlying condition, renal and overall survival prognosis with and without treatment, comorbidities, functional status, and expectations. Furthermore, treatment with immunosuppressive medications often requires frequent office visits and laboratory tests, which may significantly impact quality of life or may even not be feasible depending on the specific situation of the patient.
The treatment options often include corticosteroid therapy, which can have significant side effects, in particular difficult-to-control blood glucose levels, hypertension, central obesity, fluid retention, osteoporosis, and accelerated atherosclerosis. Depending on preexisting comorbidities, those can significantly impact outcomes and quality of life. Other treatment regimen include immunosuppressive medications that are also associated with significant comorbidities that need to be considered prior to initiation and patients need to be monitored closely and treated appropriately.
GN may require management as an inpatient to establish the diagnosis and initiate targeted therapy and continues in the outpatient setting, but requires close follow-up with frequent office visits and laboratory tests.