Mark A. Lusco

AJKD Atlas of Renal Pathology: Minimal Change Disease

Minimal change disease (MCD) is characterized by nephrotic syndrome. It is the most common cause of nephrotic syndrome in children aged 1 to 7 years and remains a cause of nephrotic syndrome in adults. Kidney function is usually preserved, except for occasional cases with acute kidney injury. MCD is typically responsive to steroids with excellent long-term prognosis. Light microscopy: Unremarkable glomeruli. Of note, global glomerulosclerosis is a nonspecific finding that can be seen. Immunofluorescence microscopy: No deposits (may have nonspecific immunoglobulin M [IgM]). Electron microscopy: Extensive foot process effacement.

Atlas of Renal Pathology IIAJKD Atlas of Renal Pathology: Minimal Change Disease

Minimal change disease (MCD) is characterized by nephrotic syndrome. It is the most common cause of nephrotic syndrome in children aged 1 to 7 years and remains a cause of nephrotic syndrome in adults. Kidney function is usually preserved, except for occasional cases with acute kidney injury. MCD is typically responsive to steroids with excellent long-term prognosis. Light microscopy: Unremarkable glomeruli. Of note, global glomerulosclerosis is a nonspecific finding that can be seen. Immunofluorescence microscopy: No deposits (may have nonspecific immunoglobulin M [IgM]). Electron microscopy: Extensive foot process effacement.

AJKD Atlas of Renal Pathology: Diabetic Nephropathy

Diabetic nephropathy is the most common cause of ESRD and develops in 20% to 30% of patients with diabetes. Time to develop overt diabetic nephropathy is typically 15 years in type 1 diabetes, with a less clear time course in type 2 diabetes (because its onset may not be known precisely). While patients typically develop albuminuria followed by overt proteinuria and glomerular filtration rate (GFR) loss, the degree of albuminuria is not necessarily linked to disease progression. Patients initially have hyperfiltration and increased GFRs, with progressive decline. Light microscopy: Classic findings include mesangial expansion mainly due to increased mesangial matrix, which can be diffuse and, as kidney disease progresses, more typically nodular (Kimmelstiel-Wilson nodules). The nodules are round with a hypocellular matrix core surrounded by patent capillary loops, resembling a sunflower. Microaneurysms of glomerular capillaries are often seen along with mesangiolysis or nodules. Segmental glomerulosclerosis, especially at the tubular outlet (ie, tip lesion), is common in later stages of diabetic nephropathy. Hyalinosis may be present within the glomerular tuft under the endothelial cells or under the parietal epithelial cells (capsular drop). Hyalinosis of afferent and efferent arterioles is common and although not pathognomonic, is rare in other conditions. In type 1 diabetes, interstitial fibrosis and tubular atrophy follow glomerular lesions and may be less severe or proportional to diabetic glomerulopathy. In type 2 diabetes, in which arteriosclerosis is commonly present, the lesions are more heterogeneous, and chronic tubulointerstitial injury may be more severe than the diabetic glomerulopathy. Immunofluorescence microscopy: Diffuse linear accentuation of glomerular and tubular basement membranes with IgG (and k and l light chains) and albumin is typical. Nonspecific segmental staining of hyaline deposits or glomerular sclerotic regions

AJKD Atlas of Renal Pathology: Light Chain Deposition Disease

Light chain deposition disease (LCDD) is the most common of the non-AL amyloid monoclonal immunoglobulin deposition diseases (MIDD), which also include subtypes with both light and heavy chains or only heavy chain component. The specific type of MIDD is diagnosed by immunofluorescence or immunohistochemistry. Patients with LCDD are middle-aged or older adults, and men are affected more often than women. The kidney is the major organ involved, often with nephrotic range proteinuria. Patients less commonly have dominant tubular basement membrane, with lesser glomerular deposits and little or no proteinuria. Patients may also show signs related to the underlying plasma cell dyscrasia, such as anemia. Other organs may be involved, such as the liver or heart, but these extrarenal deposits do not usually cause clinical signs. Some patients have concomitant light chain cast nephropathy caused by the monoclonal protein, with resulting acute kidney injury. Patients who are eligible for treatment of the underlying plasma cell dyscrasia/multiple myeloma have hematologic response in about half of cases, with corresponding stabilization or even improvement of end-organ function. Most untreated patients develop end-stage renal disease. Patients who undergo kidney transplantation despite persistent monoclonal protein develop recurrent disease in the transplant. Light microscopy: Advanced LCDD shows nodular sclerosis, with very similar appearance to diabetic nephropathy by light microscopy. Early LCDD shows only mild mesangial expansion. Congo Red stain is negative. Immunofluorescence microscopy: Monoclonal light chain staining, most commonly k light chain, in

AJKD Atlas of Renal Pathology: Immunotactoid Glomerulopathy

Immunotactoid glomerulopathy occurs in adults, on average at 60 years of age, and often presents with nephrotic proteinuria, reduced glomerular filtration rate, and hypocomplementemia in half of affected patients. Patients do not have cryoglobulins, but a circulating monoclonal paraprotein and/or lymphoplasmacytic malignancy is present in about two-thirds. Prognosis depends on the outcome of the associated disease, with half of the affected patients achieving remission with therapy directed at the malignancy. This rarely leads to end-stage kidney disease. Recurrence in transplanted kidneys has been reported. Light microscopy: Variable appearance, most commonly a membranoproliferative pattern or less frequently membranous pattern, and occasionally endocapillary proliferation. Immunofluorescence microscopy: Mesangial and chunky capillary wall immunoglobulin G, which is often clonal, and less C3, with a light chain restriction. Granular capillary loop staining is seen in cases with a membranous pattern. Electron microscopy: Microtubules, often in parallel arrays, with diameter typically .30 nm.

AJKD Atlas of Renal Pathology: Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is characterized by nephrotic syndrome and has exceeded membranous nephropathy as the most common cause of nephrotic syndrome in adults in the United States. FSGS presents similarly to minimal change disease, but is not usually responsive to steroid therapy and has progressive glomerular filtration rate loss. Light microscopy: FSGS pattern of scarring. Immunofluorescence microscopy: No or limited deposits (nonspecific immunoglobulin M and C3 staining in sclerotic areas). Electron microscopy: Extensive foot process effacement. No or limited deposits.

AJKD Atlas of Renal Pathology: IgA nephropathy.

IgA nephropathy (IgAN) presents with hematuria and varying levels proteinuria, and occurs in all age groups. The incidence of IgAN is much lower in African Americans and highest in the Asian population. The progression of disease can be rapid, especially in those with crescents. Approximately one-third of patients progress to kidney failure over time. IgAN recurs in kidney transplants in up to 60%of patients, but rarely results in graft loss. Henoch-Schönlein purpura also has mesangial IgA deposition and is morphologically similar to IgAN; however, crescents are more frequently present in biopsied Henoch-Schönlein purpura than IgAN. Light microscopy: Variable presentation from minimal mesangial expansion to diffuse proliferation; may have sclerosis and/or crescents. Morphologic markers for worse prognosis identified by the Oxford IgAN classification include significant mesangial proliferation, any segmental sclerosis or adhesion, any endocapillary hypercellularity lesion, and tubulointerstitial fibrosis .25%. Immunofluorescence microscopy: Dominant or codominant IgA mesangial staining with variable IgG and IgM. C3 is often present, usually equal or less than IgA staining. Deposits are polyclonal, often with l light chains slightly more intense than k light chains. Subendothelial deposits are often present when there is endocapillary hypercellularity. Electron microscopy: Mesangial deposits with increased mesangial matrix and cellularity. Subendothelial deposits may also be present, particularly in more active diseasewith endocapillary hypercellularity.

AJKD Atlas of Renal Pathology: Thin Basement Membrane Lesion

The thin basement membrane lesion is the underlying morphologic change in most families with benign familial hematuria and may also be seen in sporadic cases of hematuria. Many of these kindreds are carriers of autosomal recessive Alport syndrome. Patients show persistent microscopic hematuria, often with intermittent macroscopic hematuria. Of patients biopsied for persistent isolated hematuria, thin basement membranes may be present in 20% to 25%. Prognosis is generally benign, with slight increased risk of chronic kidney disease in carriers of Alport syndrome. Light microscopy: No specific lesions. Immunofluorescence microscopy: No immune complexes are seen, with normal staining for type IV collagen alpha 3, 4, 5 in carriers of autosomal recessive Alport. Carriers for X-linked Alport show mosaic staining along glomerular basement membranes (GBMs) for type IV collagen alpha 3 and 5. Electron microscopy: The lamina densa of the GBM shows marked and extensive thinning in a majority of capillary loops, compared to age-matched controls, as GBM normally increases in thickness with age. A 250 nm lower limit of normal is suggested in adults, with normal thickness in our laboratory around 110 nm at 1 year of age to 222 6 14 nm by age 7.

AJKD Atlas of Renal Pathology: Systemic Sclerosis.

Systemic sclerosis (scleroderma) has a strong predilection in women, with onset typically between ages 30-50 years. Scleroderma kidney disease occurs in 60%-70% of patients with systemic scleroderma, mostly in those with a diffuse, rather than limited, form of cutaneous scleroderma. Kidney disease is evident by hypertension, proteinuria, and loss of glomerular filtration rate. Scleroderma kidney crisis develops in about 10%-20%, and presents as new onset malignant hypertension with acute kidney injury. Antinuclear antibody is positive in .90% of these patients. Antitopoisomerase 1 and anti-RNA polymerase antibodies are often associated with kidney involvement. Patients with scleroderma kidney crisis may require dialysis. Use of angiotensin-converting enzyme inhibitors has improved prognosis of patients with kidney crisis, but mortality at 5 years remained at 30%-40%. Light microscopy: Mediumand large-sized arteries are affected by thrombotic microangiopathy. Fibrin thrombi with fibrinoid necrosis of the vessel wall without associated wall inflammation are characteristic. Intimal mucoid change, endothelial swelling, and fragmented red blood cells within the vessel wall occur acutely. Later, there is intimal proliferation, resulting in an “onion skin” concentric appearancewith luminal narrowing. Glomeruli typically show ischemic collapse, but may also have mesangiolysis and fibrin thrombi. Glomerular basement membrane duplication is present in chronic cases. Tubular injury occurs with acute injury, and tubular atrophy and interstitial fibrosis are proportional to vascular injury in the chronic stages. Immunofluorescence microscopy: Nonspecific staining for immunoglobulin M and C3 may be seen. Fibrinogen staining can be observed in glomeruli and arteries associated with fibrinoid necrosis or acute thrombotic microangiopathy.

AJKD Atlas of Renal Pathology: Sickle Cell Nephropathy

Sickle cell disease is an autosomal recessive disease that occurs most commonly in individuals of African ancestry, with an incidence of 1 in 500 African Americans. Kidney disease has varying manifestations, with microalbuminuria in childhood, progressing to overt proteinuria in 20%-25% and nephrotic syndrome in about 5%, and progressive GFR loss after age 20 years in 5%-8% of all sickle cell patients. Patients often show hyposthenuria and hematuria as well. Some patients develop papillary necrosis and acute kidney injury due to sickle cell crisis. Patients with either homozygous sickle cell disease or sickle cell thalassemia can develop any of these manifestations related to sickling. Sickle cell trait has been reported to cause sickle cell nephropathy only in rare cases. Light microscopy: Cortical infarcts can occur in sickle cell crisis due to occlusion of arteries. With chronic injury, glomerulomegaly and global and secondary segmental glomerulosclerosis are present, often in a perihilar location, with glomerular basement membrane contour duplication and corrugation. Collapsing lesions may be present related to vascular compromise resulting in ischemia. There is prominent hemosiderin deposition, seen as reddish granules in tubular epithelial cells and staining positive on Prussian blue iron stain, with focal deposition in glomerular epithelial cells. Sickled red blood cells are present, most often in medullary peritubular areas and more rarely in glomeruli. Interstitial fibrosis and tubular atrophy are present to a varying extent. Immunofluorescence microscopy: Nonspecific IgM and C3 staining in scarred glomeruli. Electron microscopy: Sickle-shaped red blood cells in glomerular and peritubular capillaries with