Renal Disease and Investigation Notes

The functional unit of the kidney is the nephron, with each kidney containing approximately one million nephrons. The upper part of the nephron is located in the cortex, while the inner part resides in the medulla. The major components of the nephron include the renal corpuscle, consisting of the glomerulus and Bowman’s capsule, a tubular system with proximal and distal convoluted tubules, collecting ducts that merge in the renal pelvis to form the ureter, and a highly vascular network to facilitate filtration and reabsorption. These nephrons are densely packed and surrounded by the tubular system and blood vessels.

The Glomerulus & Renal Corpuscle

The glomerulus is a 'tuft' of capillaries coated with a specialized basement membrane and podocyte epithelium. Bowman’s capsule is an epithelial cup-like structure that collects fluid from the glomerulus. The renal corpuscle refers to the glomerulus and Bowman’s capsule together and is a key area to analyze for the diagnosis of kidney disease. Bowman’s space collects plasma "ultrafiltrate," which then moves to the proximal convoluted tubule (PCT). The PCT is characterized by simple cuboidal epithelium with a "brush border" of tall microvilli, while the distal convoluted tubule lacks a brush border, has a clear lumen, and contains smaller cells, making more nuclei visible. The glomerulus comprises endothelial cells forming the capillaries, the mesangium with supporting mesangial cells and matrix, the glomerular basement membrane (GBM) performing the filtration function, and podocytes, which are specialized epithelial cells on the outer surface of the GBM. Filtration occurs through the basement membrane and the “filtration slits” between the “feet” of the podocytes. These podocytes are highly specialized epithelial cells that wrap around the capillaries of the glomerulus.

Disease-Associated Changes

Five common patterns of change in the glomerulus include endothelial cell proliferation, mesangial cell proliferation, basement membrane thickening, capillary wall necrosis, and crescent formation. Endothelial cell proliferation leads to occlusion of the capillary, reducing flow through the glomeruli, which correlates with oliguria and uraemia. Mesangial cell proliferation is associated with increased matrix production, leading to sclerosis and loss of capillary lumen over many years. Basement membrane thickening may be due to immune complexes or amyloid. Capillary wall necrosis results in areas of “tuft necrosis” that are eosinophilic, often fibrinoid, and may be seen in necrotising vasculitis or malignant hypertension. Crescent formation is a reaction to severe glomerular damage, characterizing rapidly progressive disease, where serum proteins and fibrin in Bowman’s capsule cause overgrowth of the epithelial lining. As the crescent enlarges, it compresses the glomerular tuft, which shrivels and becomes non-functional. Large numbers of crescents indicate a poor prognosis, usually rapid progression to renal failure, and once crescents are established, the disease type can only be determined by examining unaffected glomeruli.

Patterns of Renal Disease

Glomerular disease may not affect all glomeruli in a uniform manner; different renal diseases can affect some or all of the glomeruli in the kidney, and part or all of each affected glomerulus. These patterns of disease are described as global, segmental, diffuse, and focal. Global disease affects the whole of the glomerulus uniformly, while segmental disease affects one or more glomerular segments, leaving others unaffected. Diffuse disease affects all glomeruli in both kidneys, and focal disease affects a proportion of glomeruli, with others unaffected.

Classification of Renal Disease

Some clinical terminology includes: Acidosis (increased acidity in the blood), Anuria (non-passage of urine, <50ml/day), GBM (glomerular basement membrane), Glomerulonephritis (inflammation of the glomeruli), Glomerulonephrosis (a non-inflammatory disease of the kidney), Haematuria (presence of red blood cells in urine), Hypoabluminaemia (abnormally low levels of albumin in blood plasma), Nephritic syndrome (signs associated with inflammation in the kidney), Nephrotic syndrome (nonspecific disorder in which the kidneys are damaged), Oedema (swelling due to abnormal accumulation of fluid), Oliguria (low output of urine, 300-500ml/day), Polyuria (excessive production of urine, 2.5-3l/day), Proteinuria (an excess of serum proteins in urine), and Uraemia (high concentration of nitrogenous compounds in blood).

Partial Renal Failure, Nephrotic syndrome, Nephritic syndrome, Total Renal Failure, Acute renal failure, and Chronic renal failure are classifications of renal disease, where partial renal failure may progress to total renal failure. Acute Total Renal Failure involves the sudden cessation of the majority of nephrons, leading to oliguria, frequent anuria, acidosis, and uraemia, with the main cause being glomerulonephritis. It is often reversible if the damaging stimulus is removed unless necrosis is present. Chronic Total Renal Failure involves progressive nephron destruction over time, leading to progressive loss of renal function, less metabolic disturbance than with acute TRF, uraemia, polyuria, and biochemical changes. Potential causes include vascular disease, glomerulonephritis, and diabetes. Chronic renal failure is not reversible due to nephron destruction, and if all nephrons have been irreversibly damaged, it's known as “end-stage kidney”.

Nephrotic Syndrome

Signs & Symptoms of nephrotic syndrome include weight gain, fatigue, foamy urine, loss of appetite, oedema, proteinuria (large amounts of protein in the urine), hyperlipidemia (higher than normal fat and cholesterol levels in the blood), hypoabluminaemia (low levels of albumin in the blood), and oedema typically in the legs, feet, or ankles. It is usually a result of changes in the GBM or mesangium, with loss of selective retention of proteins in the blood leading to high levels of protein in the urine (proteinuria) and consequent loss of protein from the blood (hypoalbumenaemia) leading to oedema. Nephritic syndrome is characterized by proliferative changes in the cells of the glomerulus. Primary Causes of Nephrotic Syndrome include Minimal Change Disease and Focal Segmental Glomerulosclerosis, while Secondary Causes include Membranous Nephropathy (a.k.a. “membranous glomerulonephritis”). Glomerulonephritis is a term used to describe a group of diseases affecting the glomerulus, confusingly used for both Nephrotic & Nephritic syndromes, where the “-itis” implies inflammation, though many causes of nephrotic syndrome do not involve inflammation.

Minimal Change Disease

Minimal Change Disease shows hardly any detectable change in the glomeruli, but electron microscopy (EM) reveals a loss of podocyte ‘feet’ (pedicels). The cause (aetiology) is not well understood, though Epstein-Barr Virus and food allergies have been implicated. The appearance of microvilli and vacuolation of podocytes is also observed, leading to increased permeability of the GBM. Treatment involves immunosuppressants.

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis is characterized by scarring (scleroses) of the glomerulus. It is idiopathic in most cases but can be hereditary, with possible immune system involvement. It accounts for 10% of cases of NS in children but has a higher proportion in adults, usually indicated by heavy PAS staining and findings of IgM and C3 in the sclerotic segment, and is the most common cause of nephrotic syndrome.

Membranous Nephropathy

Membranous Nephropathy, also known as membranous glomerulonephritis, is characterized by the presence of immune complex deposits in the GBM, affecting all segments of all glomeruli (Global & Diffuse). Mainly seen in adults as a common cause of nephrotic syndrome, it leads to chronic renal failure over many years in 50% of cases, caused by immune complexes forming in the glomerulus. Sub-epithelial immune complexes develop in the glomeruli (mostly IgG), passing through 3 pathological stages: Sub-epithelial immune complex deposition in GBM, new basement membrane deposited around immune complexes, and immune complexes clear, leaving thickened ‘lacy’ basement membrane. The GBM becomes abnormally permeable, with causes including infections (e.g., hepatitis B, malaria, syphilis), drug-related factors (e.g., penicillamine, heroin), tumour-associated factors (e.g., lung cancer, lymphoma), and 10% of renal involvement in systemic lupus erythematosus is of this pattern. Where there is a recognizable cause, treatment can lead to remission.

Nephritic Syndrome

The term nephritic implies inflammation (Glomerulonephritis), involving glomerular disturbance due to proliferative changes. Reduced blood flow leads to oliguria, with some protein and blood lost in urine (proteinuria; haematuria), and uraemia is due to the retention of waste products. Important types of glomerulonephritis include IgA nephropathy (Berger’s disease), Membranoproliferative glomerulonephritis, and Post-infection glomerulonephritis.

IgA Nephropathy (Berger’s Disease)

IgA Nephropathy (Berger’s Disease) is the most common type of glomerulonephritis in adults, usually presenting as macroscopic haematuria (visibly bloody urine) within days of an upper respiratory tract or gastrointestinal infection. Biopsy shows an increased number of mesangial cells, with immuno-staining positive for immunoglobulin A deposits within the mesangial matrix. There is no explanation for IgA accumulation, and the disease is focal & segmental.

Membranoproliferative Glomerulonephritis

Membranoproliferative Glomerulonephritis is caused by immune deposits in the GBM and may be either primary or secondary (e.g., to SLE or viral hepatitis). It may present as a mixed nephrotic/nephritic syndrome, with increased mesangial cells and matrix, and basement membrane thickening. Two subtypes exist: Type II - linear dense deposits and Type I - sub-endothelial complement. It is characterized by mesangial cell proliferation, basement membrane thickening, and complement deposition.

Post-Infection Glomerulonephritis

Post-Infection Glomerulonephritis, also known as “acute diffuse proliferative glomerulonephritis,” can occur after any infection but is common after Streptococcus pyogenes. Immune complexes are filtered out by glomeruli, leading to hyperproliferation of endothelial & mesangial cells and frequently associated with crescent formation. It is characterized by the presence of immune complexes on the epithelial side of GBM, the presence of neutrophils, and complement deposition.

Histopathology of Renal Disease

Diagnosis and clinical management of renal disease often relies on biochemistry, but sometimes clinical need requires an urgent biopsy to establish a diagnosis or exclude other possibilities, ascertain the severity of the lesion (grade), and ascertain the amount of irreversible scarring (stage). In experienced hands, mortality is low, but it's painful for the patient.

Taking the Biopsy

The biopsy involves a needle biopsy with ultra-sound guidance, examined immediately under a dissecting microscope to ensure that renal cortex and glomeruli are present. The biopsy is divided into 3 parts: Standard histology (5-6mm), electron microscopy (1mm), and immunostaining (2-3mm). In theory, a single glomerulus each is adequate for EM and Immuno; glomeruli must be present for the biopsy to be usable.

Routine Stains

Routine stains include Haematoxylin & Eosin to show the cellular composition of the tissue, Methenamine silver to highlight basement membrane and connective tissue matrix, and Periodic acid Schiff, which achieves both but GBM resolution is better with meth silver.

Special Stains

Special stains include Congo red to stain for amyloid deposits, Elastin if vascular disease is suspected, and Trichrome stains (e.g., Masson’s) to show immunoglobulin deposits/fibrin (largely replaced by immunohistochemistry).

Electron Microscopy

Electron Microscopy retains importance in renal path, with approximately 60% of UK labs performing EM on all renal biopsies. EM can help refine a diagnosis, e.g., the finding of mesangial electron-dense deposits in membranous nephropathy suggests the damage is secondary (e.g., Lupus), rather than idiopathic.

Immunohistochemistry

The basic panel of antibodies in Immunohistochemistry includes immunoglobulins and complement, e.g., IgG, IgA, IgM, and usually C3 or C9. May also include antibodies to Fibrin (to detect fibrinoid necrosis and fibrin in crescents), Ig light chains (e.g., in myeloma), antibodies to viral proteins, and specific amyloid types. Methods of detection include Immunoperoxidase and immunofluorescence, both commonly used.

Summary of Clinical Features

There are 4 general rules that explain the vast majority of cases: structural change in GBM or excessive mesangial matrix deposition leads to nephrotic syndrome; glomerular damage due to proliferation of endothelial or mesangial cells leads to nephritic syndrome; damage to the basement membrane and cell proliferation leads to a mixed nephritic/nephrotic syndrome; and if damage to glomeruli is rapid, features of acute renal failure (total renal failure) develop.

Kidney Neoplasia Epidemiology & Aetiology

Kidney cancer is the 14th most common cancer worldwide and the 7th most common in the UK, with approximately 13,000 cases per year and a 5-year survival rate of 52%. The incidence has increased 87% since the ‘90s, with a projected rise of 26% by 2035. Approximately 34% of cases are considered preventable, and the incidence is linked to social deprivation in the UK. Risk factors include obesity (causing 24% of cases), smoking, kidney disease, inherited conditions (e.g., von Hippel-Lindau syndrome), family history (doubled risk), high blood pressure, and others like thyroid cancer, Type 1 Diabetes, and painkillers. Most risk is due to kidney damage.

Signs & Symptoms include blood in urine (haematuria), lower back pain, a lump or mass, abnormal red cell counts, high blood pressure, and others such as fatigue, weight loss, fever, and night sweats, but can be vague or symptomless.

Diagnosis

Diagnosis involves an ultrasound scan, cystoscopy (to check bladder), CT Urogram, and kidney biopsy.

Treatment

Treatment options include surgery (56%) involving partial or complete nephrectomy, chemotherapy (13%), radiotherapy (8%), cryotherapy or radiofrequency ablation where cancer is destroyed by freezing or heating, biological therapy using immunotherapy, tyrosine kinase inhibitors, or mTOR inhibitors, and embolisation to cut off blood supply.

Common Tumours of the Kidney

Common Benign Tumours

Common benign tumours include Renal adenoma (benign tubular epithelium; hard to distinguish from RCC), Renal oncocytoma (eosinophilic epithelium; cytoplasm filled with mitochondria), Angiomyolipomas (origin = smooth muscle of large blood vessels), and Renal fibromas (small, derived from spindle cells (fibroblasts)).

Common Malignant Tumours

90% of cases are derived from the renal tubule epithelium which are Renal Cell Carcinoma (RCC) which can be Clear Cell (‘Conventional’; ‘non-papillary’) around 75% of cases, Papillary (Chromophilic) approximately 15%, Chromophobe approximately 5%, and Transitional Cell Carcinoma originating from “Transitional” cells of the renal pelvis or ureter, with treatment similar to bladder cancer.

Less common malignant tumours (Combined, these account for 5-10% of cases of RCC) include Collecting duct carcinoma, Renal Medullary Carcinoma, Mucinous tubular & Spindle cell carcinoma, Unclassified RCC, and Nephroblastoma (Wilm’s tumour), a rare childhood tumour (approximately 80/year in UK).

Clear Cell Carcinoma

Clear Cell Carcinoma is by far the most common form of kidney cancer, named as cells show a clear cytoplasm with H&E staining, and is derived from the epithelium of the proximal convoluted tubule.

Kidney Neoplasia Prognosis

Grade

Grading uses the Fuhrman system since 1982, with grades including GX (Undetermined - Can not be assessed), G1 (Low grade - Tumour cell nucleoli small or invisible and basophilic at 400x magnification), G2 (Intermediate grade - Tumour cell nucleoli conspicuous at 400x magnification but invisible at 100x), G3 (High grade - Tumour cell nucleoli eosinophilic and clearly visible at 100x magnification), and G4 (High grade - Tumours showing extreme nuclear pleomorphism and/or containing neoplastic giant cells and/or the presence of any proportion of tumour showing sarcomatoid and/or rhabdoid dedifferentiation).

Stage

Staging is determined using the TNM (tumour; nodes; metastasis) system, shown for Clear Cell Carcinoma. T0 indicates no evidence of primary tumour. T1 indicates a tumour <7cm, confined to the kidney, with T1a being <4cm and T1b being >4cm and <7cm. T2 indicates a tumour >7cm, confined to the kidney, with T2a being >7cm and <10cm and T2b being >10cm. T3 indicates extension into major veins or perinephric tissues but not into the ipsilateral adrenal gland or beyond Gerota fascia, with T3a involving extension into renal vein branches, or invasion of perineal and/or renal sinus fat, T3b extending into the vena cava below the diaphragm, and T3c extending into the vena cava above the diaphragm or vena cava wall. T4 indicates invasion of other organs/structures, including beyond Gerota fascia (including contiguous extension into ipsilateral adrenal gland). N0 indicates no regional lymph node metastasis, N1 indicates regional lymph node metastasis, M0 indicates no distant metastasis, and M1 indicates distant metastasis has occurred. Gerota’s Fascia is a fibrous envelope of tissue that surrounds the kidney, also called Gerota's capsule and renal fascia.