C - NEPH STUDY GROUP March 12th 2014 Selected Renal Disorders Areas to be Covered • Diabetic Nephropathy • Obstructive Diseases • Renal Syndromes and Glomerular Diseases • Nephrotic • Nephritic • Interstitial Disease • Vascular Diseases Diabetic Complications • Microvascular • Retinopathy • Nephropathy • Neuropathy • peripheral & autonomic • Macrovascular • Cerebrovascular • Cardiovascular • Peripheral vascular Natural History of Type I • 5 stages • 1. Hyperfiltration at diagnosis (low s. creat) • 2. Microalbuminuria > 5-10 years (urine ACR) • 3. Overt proteinuria with BP & retinopathy for 2-5 years, minimal haematuria (MSU) • 4. CKD with normal-sized kidneys (renal U/S) • 5. ESKD 18-24 months after CKD Stage 1 Diabetes Duration 0 – 3-5 2 3-5 + 3 7-15 + 4 15-20 + 5 15 – 25+ Manifestations Renal hypertrophy ⁭ GFR Basement M thickening Mesangial expansion Microalbuminuria HPT Proteinuria HPT ↓ GFR 6 ESKD Natural History of Type II Diabetic Nephropathy • Far commoner than Type I • Long asymptomatic phase • HPT, nephropathy & retinopathy often present at time of Dx • Degree of proteinuria correlates with general vascular risk and 20x CKD risk Hyperfiltration Phase • Elevated GFR 2o • BSL/BP/protein/obesity Intra-glomerular pressure • “Too good to be true” serum creatinine • Accelerated progression to CKD Albuminuria then Proteinuria • Microalbuminuria first (lower MW) • Raised by GFR (i.e. BSL, protein diet, fever, exercise) • Spot urine ACR or PCR • more convenient than 24hr collection • more accurate than urinalysis • adjusts for fluid intake • underestimates the muscular patient Diabetic Nephropathy • From haemodynamic & metabolic stresses • Metabolic stress • deposition of advanced glycosylation end products in connective tissue & sml vessels. • May take 10-20 yrs but many T2DM asymptomatic for several yrs, hence nephropathy may already be present at Dx • 1st clinical sign is microalbuminuria (⁭⁭ACR) • Kidney not able to catabolise albumin • This can also occur transiently with • Fever • Exercise • Short term hyperglycaemia • High protein meal • Hence, repeat at a later date/rule out reversible • DM + HPT, ⁭ x 20 risk of progressive nephropathy • DM + HPT + poor diabetic & lipid control, ⁭ x 40 risk Nephropathy Risk Factors • DM Type & Duration • 20% of Type I after 20 years • 40% of Type II any duration • Poor diabetic control • Hypertension • Aboriginal > Indian > Caucasian • Smokers • Family history Nephropathy Risk Factors • Modifiable • HbA1c, BP & total cholesterol (Odds Ratio 43) • Obesity, smoking • Non-modifiable • Age, ethnicity, male sex Delaying Complications • Tight diabetic control • Prevention of microvascular Cmplx • Risk of hypos • Tight BP control • Prevention and management of micro & macro Cmplx • Use ACEI, ARB’s or both combined ACE Inhibitors can prevent progression of renal failure Normotensive Type 2 Diabetics 110 400 Proteinuria 350 320 % Initial GFR 105 (mg/day) Placebo 100 Enalapril 280 95 240 200 90 160 Placebo Enalapril 85 120 80 80 0 1 2 3 Years Ann Intern Med 118 577-581.1993 4 5 6 0 1 2 3 Years 4 5 6 Use of ACEi/ARBs • BUT: • ARF risk if underperfused • Hyperkalaemia risk with many types of pills (spironolactone) • SO: • Check BP & electrolytes at 1/12 and 6/12 • Check all new pills OBSTRUCTIVE NEPHROPATHY Obstructive nephropathy • Obstructive nephropathy is obstruction of the urinary tract at any point from the kidney top the urethral meatus. Etiology of the obstruction Within the lumen of the Urinary tract: Within the wall of the Urinary tract: Pressure on the urinary tract from outside: -Stones -Ureter neuromuscular dysfunction -Tumor (retroperitoneal, colon) -Strictures (ureter, uretoviscular) -Diverticulitis -Urethra strictures -Surgical ligation of the ureters -Pin-hole meatus -Prostate enlargement -Blood clot -Tumors in the bladder, renal pelvis & ureter In men the most common cause of obstruction is prostatic hypertrophy or cancer, stones, urethral structures In women the most common cause of obstruction is secondary to pregnancy & stones Pathophysiology Obstruction Long term intravesical pressure on the bladder Hypertrophy of the muscle wall trabeculation and cellule formation in the bladder wall mucosal diverticula detrusor muscle decompensation Inadequate emptying of the bladder Urine stasis Increases the risk for infection Back pressure on the ureter - compress the papillae Decreases GFR -Loss of nephrones Renal parenchyma Impaired renal function Ureteral wall hypertrophy trying to propel urine into the bladder Symptoms & Signs Symptoms & signs of Upper Urinary tract obstruction Symptoms & signs of lower Urinary tract obstruction Symptoms Loin pain Anuria Hematuria Physical findings Enlarged Kidney Pelvic masses that obstruct the ureter Urine extravasations presented as ascites Symptoms Straining to void Hesitancy urine stream Sense of incomplete bladder emptying Post-void dribbling Urge incontinence Supra-pubic pain Signs Supra-pubic mass Rectal Exam  enlarged prostate Meatal stenosis Investigations • Urinalysis to detect: • Pyuria : WBCs in urine that suggests inflammation • Hematouria suggesting infection, stones or tumors • Urine cytology if tumor is suspected • Serum electrolytes to detect: • Renal insufficiency by  Urea & creatinine due to GFR • Electrolyte imbalance (hyperkalemia and acidosis) due to  renal clearance of K+ and H+ • CBC to detect • anemia of chronic disease Imaging studies 1. 2. 3. Ultrasound: dilated collected system & distended bladder secondary to obstruction CT scan: Not very clear anatomical details of urinary tract. Used if external compression of urinary tract MRI: used to be able to delineate tissue planes for surgical planning. Imaging studies 4. Antegrade pyelography: direct percutaneous puncture of the pelvicalyceal system with a fine needle (22 gauge) for diagnostic opacification of the renal collecting system or for aspiration in pyonephrosis A partial obstruction in the distal ureter is caused by a small calculus Imaging studies 5. Retrograde pyelography: inject contrast directly into uretral orifice to visualize the upper collecting system. Retrograde pyelography demonstrates a narrowed ureteropelvic junction without an intrinsic mass or stone. Other studies • Cystoscopy: used to visualize the entire urethra and bladder by scope. Management • Medical therapy (supportive therapy) • Analgesics • Antibiotics Surgical therapy (definitive therapy) • Surgical therapy for lower Urinary tract • Urethral catheter: catheter is placed through the urethral meatus into the bladder. It is an absolute contraindication if bladder damage is suspected. • Supra-pubic catheter: insert the catheter into the bladder directly from the anterior abdominal wall. Urethral catheter Supra-pubic catheter Surgical therapy (definitive therapy) • Surgical therapy for upper Urinary tract • Ureter stents: endoscopicaly placed tube from the renal pelvis to the bladder • Percutaneous nephrostomy: small tube placed in the renal pelvis, ureter, bladder. Ureter stent Percutaneous nephrostomy Post-operative considerations • After the relieve of a long standing obstruction, diuresis occur due to: • Water overload • Osmotic affect of retained salt • Defect in the renal reabsorption capacity • Diuresis is self-limiting but some patients may develop severe hyponatremia, hypokalemia, alkalosis & dehydration & may require IV replacement. Complications • Urinary tract infection • Urinary extravasations • Renal parenchyma loss  renal insufficiency and renal failure • Bladder decompensation  neurogenic bladder Renal Syndromes • Asymtpomatic Urinary Abnormalities • Proteinuria • Hematuria • Nephrotic Syndrome • Nephritic Syndrome • Acute Kidney Injury • Chronic Kidney Disease OBJApproach to Glomerular Diseases ECTIVES • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation • General Principles of Management Afferent arteriole Parietal EC Capillary loop Endothelium Macula densa Mesangium JG cells Urinary space Efferent arteriole Visceral EC Mesangium Normal Glomerulus Normal glomerulus PADefinition of Terms THOLOGY • Glomerulopathy vs. Glomerulonephritis • Primary vs. Secondary • Diffuse vs. Focal • Global vs. Segmental • Fibrosis vs. Sclerosis • Membranous vs. Proliferative • Endocapillary vs. Extracapillary Fibrosis – increase in the deposition of collagen fibers Sclerosis – increase in the amount of homo-genous nonfibrillar extracellular material Sclerosis Segmental – lesion involves < 50% of the glomerulus Sclerosis Global – lesion involves > 50% of the glomerulus Sclerosis Diffuse Global Glomerulosclerosis Focal – lesion seen in less than 50% of glomeruli Diffuse – lesion seen in more than 50% of glomeruli Mesangial cells Normal glomerulus Proliferation – increase in the glomerular cell number Mesangial cells Mesangial proliferativeGN Endocapillary proliferation Extracapillary proliferation Normal glomerulus Membranous – expansion and thickening of the glomerular basement membrane (GBM) by immune deposits Primary Mechanisms of Glomerular Injury Mechanism of Injury Renal Insults/ Defects Glomerular Disease Immunologic Immunoglobulin Immune-complex GN Goodpastures Cell-mediated injury Pauci-immune GN Cytokine Primary FSGS Complement activation MPGN Type II Hyperglycemia DM Nephropathy Fabry’s disease/ sialidosis FSGS Systemic hypertension HTN Nephrosclerosis Intraglomerular hypertension Secondary FSGS Metabolic Hemodynamic Primary Mechanisms of Glomerular Injury Mechanism Renal Insults/ Defects of Injury Glomerular Disease Toxic E. coli-derived verotoxin Thrombotic microangiopathy Therapeutic drugs (NSAIDs) Minimal change disease Recreational Drugs (Heroin) FSGS Deposition Amyloid fibrils Amyloid nephropathy Infectious HIV HIV Nephropathy Subacute Endocarditis Immune complex GN Inherited Genetic defect for α5 chain of Alport’s Syndrome type IV collagen Abnormally thin basement membrane Thin basement membrane disease Immunologic Glomerular Injury Humoral Antibody-Mediated Injury • Autoantibodies against intrinsic antigens (example: Goodpasture’s syndrome) • Autoantibodies against extrinsic “trapped antigens (example: Postinfectious GN) • Trapping of circulating immune complexes (example: Cryoglobulinemic GN) Cellular Mediated Injury GN Loss of nephrons Glomerular hyperfiltration Glomerular HTN Non-selective prtoteinuria Glomerular sclerosis Tubulointerstitial inflammation Ischemia Tubulointerstitial atrophy/fibrosis Two Final Common Pathways in Glomerular Injury Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation • General Principles of Management Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation Syndrome Diagnosis History Physical Examination Ancillary Laboratory Tests • Chemistry • Serology • Urinalysis Syndromes in Glomerular Diseases Syndrome Clues to Diagnosis Common Findings Rapidly Progressive Renal Failure (RPRF) Anuria Oliguria Decline in GFR over weeks HTN, Hematuria, Proteinuria, Pyuria Nephritic Syndrome Hematuria, RBC casts, Azotemia, Oliguria, Edema, HTN Proteinuria, Syndromes in Glomerular Diseases Syndrome Clues to Diagnosis Common Findings Nephrotic Syndrome Proteinuria > 3.5 gms Hypoalbuminemia Hyperlipidemia Lipiduria Casts Edema Asymptomatic Isolated hematuria urinary Isolated proteinuria abnormality (AUA) Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation Clinicopathologic Correlation Syndrome Diagnosis Histologic Diagnosis Etiologic Diagnosis Nephritic Diffuse Immune complex GN (>70%)* Proliferative GN Pauci-immune GN (<30%)** Nephritic Nephrotic MembranoImmune complex GN* Proliferative GN Thrombotic microangiopathy RPRF Crescentic GN Isolated hematuria Mesangial IgA nephropathy Proliferative GN HSP Immune complex GN (≅45%)* Pauci-immune GN (≅45%)** Anti-GBM disease (≅10%) * SLE, Postinfectious GN, IE, Cryoglobulinemia ** Wegener’s granulomatosis, Microscopic PAN Clinicopathologic Correlation Syndrome Histologic Diagnosis Diagnosis Etiologic Diagnosis Nephrotic Minimal Change Disease (MCD) Idiopathic, drugs, heroin, HIV, lymphoma Nephrotic Focal Segmental Glomerulosclerosis (FSGS) Idiopathic, HIV, heroin, secondary forms from reduced nephron number Nephrotic Membranous Glomerulopathy Idiopathic, infections, drugs, autoimmune diseases, paraneoplastic syndrome Nephrotic CRF Nodular sclerosis DM nephropathy Chronic GN Clinical Diagnosis Disease Renal Syndrome Clinical Features Diabetic nephropathy Nephrotic CRF Chronic course, (+) DM retinopathy, nl-sized kidneys, bland urine sediment Goodpasture’s syndrome Nephritic RPRF antiGBM-aby (+), cANCA (-), nl C3 Nephritic Wegener’s granulomatosis RPRF antiGBM-aby (-), cANCA (+), nl C3 Clinical Diagnosis Disease Renal Clinical Features Syndrome Lupus nephritis Nephritis RPRF antiGBM-aby (-), cANCA (-), low C3, ANA (+), (+) ACR criteria for the diagnosis of SLE Poststreptococcal Nephritis GN antiGBM-aby (-), cANCA (-), low C3, ASO (+), prior Streptococcal infection Sample Case • 28 year old female referred for acute onset of pedal • • • • • • edema X 1 week No other associated signs and symptoms Single; sexually active; silent past medical history; not on any medications; no history of IVDA ROS: denies other symptoms Well-nourished, not obese BP = 120/80, clear BS Grade III pedal edema SAMPLE CASE • Serum creatinine = 70 umol/l EGFR 90 mls/min (nl) • Albumin = 20 mg/mL (low); Cholesterol = 8 umol/l (high); FBS = 6 umol/l (nl) • CXR: normal; UTS of kidneys: normal • Urinalysis: +4 protein, 0-1 RBC/hpf, 0-1 WBC/hpf, no casts • 24-hour urine study: creatinine clearance of 98 cc/min and proteinuria of 4.5 g/day Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation SAMPLE CASE What is the renal syndrome present? • Nephritic syndrome • Nephrotic Syndrome • Rapidly progressive renal failure • Asymptomaric urinary abnormality SAMPLE CASE Answer: Nephrotic syndrome • Edema • Hypoalbuminemia • Hyperlipidemia • Proteinuria > 3.5 g/day Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation SAMPLE CASE Is it possible to make a clinical diagnosis? • Yes or No ? • If yes, what is your clinical diagnosis? • If no, is a kidney biopsy indicated? SAMPLE CASE Answer: No • No signs of systemic disease, ROS negative for other symptoms • PE normal except for edema • Normal FBS • Adult nephrotic syndrome – unlike children, no room for empiric steroid therapy • Kidney biopsy indicated Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation Sclerosis Foot process fusion SAMPLE CASE Histologic Diagnosis: • Focal segmental glomerulosclerosis Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation SAMPLE CASE • What are the possible causes of FSGS? • What additional test/s is/are needed? • Is this primary vs. secondary FSGS? Etiology of FSGS Idiopathic (Majority) Systemic Diseases or Drugs • HIV • Diabetes mellitus • Fabry’s disease • Sialidosis • Charcot Marie-Tooth Disease • Heroin Etiology of FSGS Congenital Oligonephropathies Acquired nephron loss • Surgical resection • Reflux nephropathy • Chronic GN/ renal disease Other adaptive responses • Sickle-cell nephropathy • Obesity with sleep apnea • Familial dysautonomia SAMPLE CASE • No signs of systemic diseases • No history or sign (normal kidneys on UTS) of • • • • • nephron loss Not obese No history of IVDA/ heroin use Sexually active – need to rule out HIV HIV ELISA test ordered – negative Final diagnosis: Idiopathic Primary FSGS OBJECTIVES Introduction Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation General Principles of Management General Principles of Management • Disease-specific therapy for primary and secondary GN • Therapy to retard the progression of disease • Therapy to address complications Disease-specific therapy GN Loss of nephrons Glomerular hyperfiltration Glomerular HTN Non-selective prtoteinuria Glomerular sclerosis Tubulointerstitial inflammation Ischemia Tubulointerstitial atrophy/fibrosis Two Final Common Pathways in Glomerular Injury Disease-Specific Therapy for Primary (Idiopathic) GN Syndrome Disease Therapy Nephritic MPGN Aspirin plus dipyridamole Nephrotic MCD Steroids Nephrotic FSGS Steroids Nephrotic Membranous Steroids plus chlorambucil (Ponticelli protocol) Disease-Specific Therapy for Secondary GN Syndrome Disease Therapy Nephritic Poststreptococcal GN Penicillin; supportive RPRF Wegener’s granulomatosis Steroids plus PO cyclophosphamide RPRF Goodpasture’s syndrome Plasmapharesis Nephritic Lupus nephritis IV Steroids, IV cyclophosphamide Nephrotic Hep B membranous GN Interferon Nephrotic MCD due to NSAIDs Discontinue offending drug GN Loss of nephrons Glomerular hyperfiltration Measures to delay progression Glomerular HTN Non-selective prtoteinuria Glomerular sclerosis Tubulointerstitial inflammation Ischemia Tubulointerstitial atrophy/fibrosis Two Final Common Pathways in Glomerular Injury Renoprotective Strategies (Hebert, 2000) • Control blood pressure (< 127/75). (1) • Use of ACE-I for BP. (1) • Control of blood glucose for diabetics.(1) • Limit protein intake to 0.8 g/kg IBW/day.(1) • Limit NaCl intake (2-3 g/day).(3) • Control lipids using statins (HMG-CoA reductase inhibitor therapy). (2) • Avoid cigarette smoking. (2) • Avoid regular intake of NSAIDs.(3) ( ) Level of Recommendation Renoprotective Strategies (Hebert, 2000) • Control plasma homocysteine level using folic acid • • • • • • • (2-15 mg/d). (3) Control hyperinsulinemia (exercise and weight reduction). (3) Use of antioxidants (Vit C and Vit E). (3) Correct anemia (HgB 11-12). (2) Avoid hypokalemia. (3) Control hyperphosphatemia. (3) Low dose ASA. (3) Estrogen replacement for women. (3) ( ) Level of Recommendation Treatment of Complications • Diuretics to control edema. • ACE-I/AII-RBs to control BP. • Anticoagulants (warfarin) for hypercoagulable states. • Statins for hyperlipidemia • Measures to prevent osteoporosis for patients on steroids (Calcium, Vit D, biphosphonates). • Co-trimoxazole to prevent Pneumocystic pneumonia for patients on steroids SUMMARY Introduction Approach to Glomerular Diseases • Syndrome Diagnosis • Clinical Diagnosis • Histologic Diagnosis • Clinicopathologic Correlation General Principles of Management DISEASES OF THE RENAL TUBULE AND INTERSTITIUM Two very broad groups of conditions 1. Acute tubular necrosis (ischaemic or toxic necrosis of tubular cells) 2. Tubulointerstitial nephritis (a.k.a. interstitial nephritis) (inflammatory reactions involving the tubules and/or interstitium) Acute tubular necrosis (ATN) • important cause of acute renal failure • characterized by acute destruction of tubular epithelial cells • most commonly secondary to ischaemia, but can also be due to direct toxic cell damage • potentially reversible, since tubular cells can regenerate given time ATN due to ischaemia • due to 1) “shock” (rapid uncompensated fall in systemic BP) e.g. in trauma, burns, falciparum malaria, pancreatitis, sepsis, DIC, blood transfusion reactions etc OR 2) reduction in intrarenal blood flow (RPGN, acute interstitial nephritis, urinary obstruction) • remember, tubular blood flow is from postglomerular capillary bed - and tubules are metabolically very active, thus susceptible to ischaemia ATN due to toxins • heavy metals – Pb, Au, As, Cr etc • organic solvents – CCl4, chloroform • drugs – antibiotics (espec gentamicin), anti-viral agents, NSAIDs, mercurial diuretics • iodinated contrast agents used for X rays • pesticides • glycols – ethylene glycol In both types of ATN • tubular cell degeneration and death • tubular casts of dead cells & debris • (may be accompanied by myoglobinuria in crush injury or Hb/uria in haemolysis) • interstitial oedema & secondary inflammation • pale swollen kidneys ATN causes acute renal failure Clinically variable, but classically in 3 phases – 1. 2. 3. initial (~ 36 hrs) (often missed) – slight increase in urine output and rise in serum urea oliguric – urine output 400 ml or less/day, so Na+, K+ & water retention, rising urea, metabolic acidosis – danger of pulmonary oedema & cardiac dysrhythmias diuretic – urine output above normal, so loss of water, Na+ & K+ – danger of dehydration Complete recovery possible Renal cortical necrosis • more severe effect of shock on the kidneys than ATN • • • • produces also caused by rapid uncompensated fall in systemic BP (“shock”) but, in this situation, hypotension so severe that renal blood flow diverted into medullary vasa recta away from cortex so whole cortex becomes infarcted irreversible (Tubulo)interstitial nephritis • heterogeneous group of conditions • similar morphology and clinical features, but wide variety of causes • other than acute infective cases, T cell reaction probably involved in most • some agents (e.g. certain drugs) can cause ATN in some patients, interstitial nephritis in others (and even GN in still others!): not clear why • interstitial nephritis can be clinically overshadowed by other systemic manifestations of primary cause/condition Causes of interstitial nephritis 1 • immunological reactions, notably • hypersensitivity reactions • transplant rejection • infection • especially pyelonephritis • direct toxic damage • drugs, particularly analgesics • heavy metals • metabolic diseases, e.g. gout Causes of interstitial nephritis 2 • physical factors • urinary tract obstruction • radiation nephritis • neoplasia, particularly myeloma kidney • vascular diseases, including • hypertension (also causes glomerular damage) • papillary necrosis • etc etc • in many cases, precise cause never identified Analgesic nephropathy • excess & long-term intake (“abuse”) of analgesic mixtures • especially aspirin (ischaemic effect) & phenacetin (toxic effect) • chronic accumulative damage • chronic interstitial nephritis, often with renal papillary necrosis as the initial feature • more common in women • headache, anaemia, hypertension and GI symptoms are common • rarely, carcinoma of renal pelvis supervenes Myeloma kidney • the most common example of “cast nephropathy*” • protein casts block tubules, causing them to rupture producing tubulointerstitial nephritis • due to glomerular filtration of Bence-Jones protein (light chains) • in myeloma, kidneys may also show • (primary) amyloidosis • pyelonephritis secondary to UTI • calcification (“metastatic” type) secondary to bone disease • glomerular lesions because of trapped Igs • *“cast nephropathies” – associated with diseases producing abnormal plasma proteins which tend to block renal tubules Vascular diseases and the kidney • Nephrosclerosis – benign & accelerated • Renal artery stenosis • Infarcts • Cortical necrosis • Sickle cell disease • Haemolytic uraemic syndrome – ATN in severe haemolysis