CHAPTER 28

Nephrotic and Nephritic Renal Disease

Hillary Wall, PharmD

Glomerular disease is the third largest cause of chronic renal insufficiency in the United States. The U.S. Renal Data System (USRDS) reports that glomerular nephritis continues to be the third leading cause of end-stage renal failure (USRDS, 2012). Glomerular diseases are similar in that they are all related to abnormalities within the glomerulus. However, the glomerulopathies constitute a somewhat diverse group of disorders in terms of prevention, presentation, prognosis, and treatment (Lewis & Neilson, 2011). Although glomerular diseases often ultimately require renal biopsy for diagnosis, careful evaluation of a patient’s history, family history, physical examination, clinical laboratory results, renal imaging, serology, urinalysis, and age may allow the provider to narrow the diagnosis significantly. This chapter is intended to give an overview of glomerular disease. Should the primary care provider (PCP) find that he or she is managing a patient with glomerular disease, it would be prudent to refer that patient to a specialist in nephrology.

ANATOMY, PHYSIOLOGY, AND PATHOLOGY

A comprehensive review of the anatomy and physiology of the kidney appears in the chapters on acute and chronic kidney disease (Chapters 26 and 27).

The glomerulopathies are often confusing in that they may be grouped according to their histology, cause, presentation, type of urinary sediment, or some combination of all of these (Lewis & Neilson, 2011). Glomerulopathies are categorized as primary or secondary. Primary glomerulopathies originate in the glomeruli of the kidney. Secondary gl omerulopathies are a consequence or complication of a systemic disease (Table 28.1).

The strong association of primary glomerulopathies with certain diseases suggests that some are in fact systemic diseases that are limited to the kidney. Histologically, the patterns observed in the kidney generally cannot differentiate primary from secondary glomerulopathies. Ultimately, the diagnosis of any given kidney disease relies on the amalgamation of histology (light, immunofluorescent, electron), serology, clinical presentation, and genetics.

Glomerular disease may also be assigned to a nephrotic or nephritic category, based primarily on urinary findings. This chapter discusses the more common causes (both primary and secondary) of nephrotic and nephritic glomerular disease.

MINIMAL CHANGE DISEASE OR NIL DISEASE

Minimal change disease (MCD) accounts for about 10% to 15% of all cases of nephrotic syndrome in adults, 90% in children less than 10 years of age, and 70% in greater than 10 years (Lewis & Neilson, 2011). Light microscopy reveals normal or minimal changes in the mesangial cell proliferation. Immunofluorescence studies do not reveal antibody deposits. Electron microscopy shows loss of foot processes on visceral epithelial tissue. MCD is likely a disorder of T cells, which produce a cytokine that injures the podocyte and the capillary in the glomerular tissue (Lewis & Neilson, 2011). Most of the cases are idiopathic in origin. Some occurrences are attributed to drugs, including nonsteroidal anti-inflammatory drugs (in particular fenoprofen), lithium, tiopronin, ampicillin, rifampin, bisphosphonates, and interferon (Loh & Cohen, 2009). Malignancy, in particular Hodgkin’s lymphoma, has also been associated with MCD. The tumor is thought to produce cytokines that are lethal to the glomerular epithelial cells. Secondary MCD responds well to removal of the cause or treatment of the underlying disease.

Usually patients with MCD present with edema and proteinuria in the nephritic range (>3.5 g/d), though renal function is usually within normal range. Symptoms develop quickly. Hypertension is noted in about 30% of adults with MCD, but is seen in only 15% of children, who may even present with hypotension. Other symptoms include ascites, pleural effusions, peritonitis, hypercholesterolemia, and thromboembolism. Prior to the use of corticosteroids, infections were the primary cause of death in patients with MCD. Most patients improve with use of the corticosteroids prednisone or prednisolone orally as a single daily dose of 1 mg/kg (maximum of 80 mg) or alternate-day single dose of 2 mg/kg (maximum dose of 120 mg) for a minimum of 4 weeks if complete remission is observed and up to 16 weeks if remission is not seen. The dose should then be tapered slowly over 6 months. In patients with frequently relapsing MCD, and those who are steroid dependent or intolerant to corticosteroids, cyclophosphamide or the calcineurin inhibitors may be used (KDIGO, 2012). Although relapse is common, overall the prognosis for patients with MCD is good. Progression to end-stage renal disease (ESRD) is unusual (Lewis & Neilson, 2011).

TABLE 28.1

Systemic Diseases Associated With Secondary Glomerular Nephropathies

Endocrine

Diabetes

Oncologic

Multiple myeloma

Lymphoma

Leukemias

Carcinomas

Hematologic

Sickle cell disease

Thrombotic thromb-ocytopenia purpura

Connective tissue

Systemic lupus

Polyarteritis

Wegener’s granulomatosis

Scleroderma

Mixed connective tissue disease

Henoch–Schönlein purpura

Behçcet’s

Sjögren’s syndrome

Infectious

Poststreptococcal

Hepatitis B and C

Endocarditis

Other

HIV

Drugs

MEMBRANOUS GLOMERULONEPHRITIS (OR NEPHROPATHY)

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. The majority of cases diagnosed are idiopathic, although cases associated with hepatitis B infections, malignancy, systemic lupus erythematosus, and drugs (such as penicillamine and gold) have been reported (Lewis & Neilson, 2011). The pathology is thought to be related to antibodies to a podocyte protein. Light microscopy may reveal thickened glomerular basement membranes. Immunofluorescent microscopy shows deposits of IgG and sometimes C3. Electron microscopy displays thick densities on the capillary loops and effacement on the podocyte (Adler & Salant, 2003). MN affects more males than females, and is most likely to occur in the fourth to fifth decades of life. Clinically, most patients present with edema and nephrotic-range proteinuria. Hematuria is seen in about half of patients. Mild hypertension may be noted in some patients. Increased plasma creatinine concentrations are seen in patients with advanced disease, and these patients are also more likely to have hypertension. Hypercoagulopathy is a recognized complication of all the nephropathies, but the risk is increased in MN (Couser & Cattran, 2010; Lewis & Neilson, 2011).

The natural history of MN is variable. It is estimated that 25% to 50% of patients presenting with nephrotic syndrome will develop ESRD within 10 to 15 years from diagnosis. Other patients have a very benign course, characterized by spontaneous remissions. As with most of the glomerulopathies, long-term studies on outcome and progression to kidney disease are limited. The variability in the natural course of the disease makes the evaluation and selection of therapy both difficult and controversial (Couser & Cattran, 2010). Factors that are associated with increased risk of progression to ESRD include male gender, age >50 years, proteinuria >8 g/d, increased plasma creatinine at the time of presentation, interstitial fibrosis seen on biopsy, and hypertension (Couser & Cattran, 2010). Conventional treatment is focused on management of blood pressure (BP), proteinuria, edema, and hyperlipidemia. Patients at high risk for developing progressive kidney disease may benefit from a 6-month course of a combination of corticosteroids and an oral alkylating agent (Couser & Cattran, 2010; KDIGO, 2012).

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Focal segmental glomerulosclerosis (FSGS) is notable for scarring or sclerosing of the glomeruli. “Focal” refers to the fact that not all the glomeruli are involved. It is more common in African Americans and there is an increased incidence in males. It is one of the primary glomerulopathies, so the majority of cases are thought to be idiopathic. However, systemic diseases are also associated with FSGS. FSGS is associated with HIV1; parvovirus; cytomegalovirus (CMV); obesity; and drugs, including pamidronate, heroin, lithium, anabolic steroids, and interferons (Markowitz, Nasr, Stokes, & D’Agati, 2010). The likely pathology in hereditary FSGS is injury to the podocyte, perhaps by a T-cell mediated factor that affects permeability. Light microscopy shows sclerotic and hyalinotic features in the glomerular tuft. Immunofluorescent microscopy is normal except for IgM and C3 in the sclerotic lesions. Electron microscopy shows widespread effacement of the foot processes and deterioration of the podocytes (Adler & Salant, 2003; Appel & D’Agati, 2010; Markowitz et al., 2010).

Patients with FSGS usually present with proteinuria in the nephrotic range, edema, impaired renal function, and hypertension. Red cells and red cell casts can be observed in the urine sediment. Many of these patients progress to ESRD. Risk factors for progression to ESRD include nephrotic-range proteinuria, African American race, and increased serum creatinine at time of diagnosis (Lewis & Neilson, 2011). Some patients who initially present with MCD may degenerate to FSGS (Ijpelaar et al., 2008). Initial management of patients with FSGS with clinical presentation of nephrotic syndrome is corticosteroids, 1 mg/kg of prednisone or prednisolone orally (maximum of 80 mg or 2 mg/kg) as a single dose on alternate days (maximum of 120 mg) for 4 weeks minimum up to 16 weeks and then slow taper over 6 months. Calcineurin inhibitors (e.g., cyclosporine or tacrolimus) have also been used in patients with contraindications or intolerance to corticosteroids. For patients with secondary FSGS, treatment should generally be directed at management of the underlying cause (Markowitz et al., 2010; Radhakrishnan & Cattran, 2012).

DIABETIC NEPHROPATHY (DIFFUSE AND NODULAR GLOMERULOSCLEROSIS)

Diabetic glomerular disease is the most common cause of end-stage kidney disease (ESRD) requiring dialysis (USRDS, 2012). The risk of developing diabetic nephropathy in those with type 1 diabetes (T1DM) and type 2 (T2DM) diabetes appears to be genetically mediated. The risk for developing ESRD for type 1 and type 2 diabetics is similar, with an incidence of about 50% after 30 years of disease. The higher incidence of the latter means that the majority of individuals with ESRD have T2DM. Diabetic nephropathy is described as a diffuse and nodular glomerulosclerosis. Diffuse thickening in the glomerular basement membrane is observed with the light or electron microscope in patients with diabetic nephropathy.

Kimmelstiel–Wilson lesions are nodules that can be seen in more advanced stages of diabetic renal disease in light microscopy. Immunofluoroscent microscopy may show deposition of IgG in a linear pattern. Renal biopsies from both T1DM and T2DM are similar (Lewis & Neilson, 2011). The exact mechanism of diabetic glomerular disease is not clearly understood. One theory is that advanced glycosylation end products (produced by the glycosylation of proteins) accumulate and alter the mesangial matrix (Lewis & Neilson, 2011; Ritz & Wolf, 2010). Diabetic nephropathy develops in stages: initially patients are noted to have an increase in glomerular filtration (hyperfiltration), then microalbuminuria and then proteinuria. Increased glucose concentrations may contribute to increased pressures within the glomerulus, which are detrimental. The onset of overt diabetic nephropathy is usually about 15 years after the initial renal changes and ESRD about 25 years after (Lewis & Neilson, 2011; Ritz & Wolf, 2010).

Clinically, patients with diabetic nephropathy may initially present with microalbuminuria, with proteinuria occurring later in the course of disease, and that proteinuria can be in the nephrotic range. Patients with diabetic nephropathy typically have normal to enlarged kidneys on ultrasound. Conversely, small kidney size is seen in nondiabetic causes of glomerular disease. Diagnosis of diabetic nephropathy may be made without a renal biopsy in many patients, but the practitioner is cautioned that diabetics may have other causes of renal disease (Ritz & Wolf, 2010; Lewis & Neilson, 2011). Strict glycemic, BP, and lipid control in this group is critical (Ritz & Wolf, 2010; Lewis & Neilson, 2011).

AMYLOIDOSIS

Patients with renal amyloidosis usually present with severe proteinuria, severe edema, and low albumin concentrations. Multiple organ involvement is often observed. Patients may present with hepatosplenomegaly; congestive heart failure; gastrointestinal, cutaneous, or nerve disease; and/or carpal tunnel syndrome. Initially, the plasma creatinine concentration may be normal or moderately elevated. This can often progress rapidly to ESRD. The pathogenesis is thought to be related to deposits of beta-pleated amyloid fibrils in the glomeruli, renal vasculature, and interstitium. In primary amyloid disease, amyloid L is deposited. Amyloid A is seen in secondary disease. Secondary disease has been associated with multiple myeloma, tuberculosis, rheumatoid arthritis, familial Mediterranean fever (FMF), chronic infection, and chronic inflammation. Primary amyloidosis is the most likely diagnosis in patients over 40 years of age. The prognosis and treatment options for primary amyloidosis are limited. Treatment of amyoid L has included high-dose melphalan with autologous stem cell transplant. More recently, some trials with mephalan and high-dose dexamethasone have shown promise in some patients (Palladini et al., 2007). Treatment of the cause(s) of secondary amyloidosis (e.g., infection) may lead to its resolution and thus a more favorable outcome for organ health (Gertz et al., 2005).

Nephritic Glomerular Diseases

IMMUNOGLOBULIN A NEPHROPATHY (IgAN, BERGER’S DISEASE)

IgAN, or Berger’s disease, is the most common type of glomerulonephritis worldwide. Granular IgA deposits observed under immunofluorescence are diagnostic for Berger’s disease. Approximately half of patients with IgAN have high plasma IgA concentrations. Though the clinical picture may vary, IgAN typically presents with intermittent gross hematuria and flank pain. Often the diagnosis is made when mild proteinuria and microscopic hematuria are noted on a urinalysis. In almost half of the patients who present with IgAN, an infection (often upper respiratory) has occurred within the last week. IgA is considered to have a better outcome than some of the other glomerulopathies, although ESRD may develop in 20% of patients within 20 years of diagnosis. Factors that have been suggested to increase the chance for developing ESRD are increased plasma creatinine concentration, uncontrolled hypertension, urinary protein excretion >1 g/d, or morphological glomerular scarring, crescent formation, or tubule-interstitial changes. The natural history of IgA is generally favorable, taking 10 to 20 years to develop into ESRD, if the latter occurs at all (Cattran et al., 2009; Feehally & Floege, 2010). Initiate antiproteinuric and antihypertensive therapy based on KDIGO guidelines (KDIGO, 2012). Henoch–Schonlein purpura nephritis (HSP) has a pattern on immunofluorescent microscopy that is similar to IgA nephritis. HSP is primarily seen in children and presents with triad of purpura, abdominal pain, and hematuria. Renal prognosis for children with HSP is generally favorable (Adler & Salant, 2003; Feehally & Floege, 2010).

Alport’s Syndrome

Alport’s syndrome is an X-chromosome-linked disorder associated with hearing loss and lenticular opacities. It is usually identified at birth or during the neonatal period. Males often progress to ESRD in late adolescence. Females tend to have a more benign course. Histologically, thinning of the glomerular basement membrane is observed early in the disease course. Later, splitting or laminating of the basement membrane is more diagnostic of Alport’s syndrome. Asymptomatic hematuria and proteinuria or gross intermittent hematuria are typically seen early. Although family history of deafness favors the diagnosis of Alport’s over IgAN, disease presentation may be quite similar in other respects (Adler & Salant, 2003; Kashtan, 2010).

POSTINFECTIOUS GLOMERULONEPHRITIS