Renal circulation

Arteries (down) Abdominal aorta Renal artery Segmental arteries Lobar arteries Interlobar artery Arcuate arteries Interlobular artery Afferent arterioles Glomerulus Veins (up) Vena cava Renal vein Interlobar vein Arcuate vein Interlobular vein Efferent arterioles Glomerulus

 100 times greater blood flow than other organs of the body 25 % of the total blood flow >90% of blood passes through the glomerulus Cortical glomeruli: High pressure capillary network in glomerulus. Blood flowing through the peritubuler capillary is deprived of water content

 Two successive capillary network More RBC in cortical glomeruli Uneven blood flow Juxta medullary Glomerulus: Not affected by systemic BP Less oxygen is required for medulla Blood flow to kidney is regulated by RAS and by Na concentration in DCT (Macula densa)

What is kidney damage ?

Structural abnormalities: Pathological, Radiological

Functional abnormalities: Composition of blood and/or urine

Urine Protein
Urinary protein >150mg/day abnormal Urinary Albumin >30 mg/day abnormal Micro-albumin 30-300mg/day(Measured using ELISA or radio-immunoassay) Albumin > 300mg/day can be measured by dipstick or albustix.

Dipsticks are semiquantitative. As a rough guide .Trace ~ 0.15-0.3 g/L

....+ .++ ....+++ .++++ ~0.3 g/L ~ 1 g/L ~ 2.5-5 g/L > 10 g/L

Albumin:Creatinine Ratio First morning sample is usually preferable Urinay excretion of creatinine is constant(~10 mmol/day) If urine albumin is 30 mg/day to 300 mg/day ACR will be 3 to 30 mg/mmol Micro-albuminuria If > 300 mg to < 3500 mg then ACR is > 30 to < 350 mg/mmol Overt Proteinuria If ACR > 350 mg/mmol Nephrotic

Urine RBC
Haematuria 2 rbc/hpf in spun urine Dipsticks are as sensitive as microscopy Microscopy is the gold standard Dysmorphic RBC indicates glomerular bleeding.

Cell/Casts
Leucocytes - May be a feature of TIN Lymphocytes feature of Chronic TIN Eosinophils(hansels or wrights stain)associated with TIN, also possible in RPGN. Renal tubular cells- ATN, TIN Casts are Tamm-Horsfall mucoprotein within the renal tubules conferring a characteristic cylindrical shape.

 Hyaline casts: nonspecific Granular casts: most of the time nonspecific Red cell cast: Diagnostic of GN WBC casts: Acute PN and TIN

Blood tests
S. Creatinine convenient indirect measure of GFR- derived from metabolism of creatine in skeletal muscle. Little short term variation. S. Urea disproportionate increase in prerenal renal dysfunction

What is GFR ?
Volume of plasma filtered by all nephrons of both kidneys per minute. 1.2 millions of nephrons in each kidney. MW- 65,000 daltons

 Creatinine clearance = Y ml/min Plasma concentration of creatinine = 1 mg/dl=0.01 mg/ml Urine volume in 24 hrs = 1440 ml Urine concen. of creatinine = 1 mg/ml Amount of creat in urine= 1440 ml x 1 mg/ml= 1440 mg Y ml/min x [24x 60] min x 0.01 mg/ml = 1440 mg Y ml/min x 1440 min x 0.01 mg/ml = 1440 mg 1440 Y ml x 0.01 mg/ml = 1440 mg 14.40 Y mg = 1440 mg > Y =1440/14.40=100

 Decreased GFR without kidney damage: Individuals with GFR 60 to 89 mL/min/1.73 m2 without kidney damage are classified as decreased GFR. Older patient (global glomerular sclerosis and cortical atrophy). Vegetarian diets, unilateral nephrectomy, extracellular fluid volume depletion, and systemic illnesses associated with reduced kidney perfusion, such as heart failure and cirrhosis

 In 2002, K/DOQI:
Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2) Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2) Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2) Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2) Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis) In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities on imaging studies, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease.

Pathophysiology
In the face of renal injury (regardless of the etiology), the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons, by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons.

 The hyperfiltration and hypertrophy of residual nephrons, a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to secondary focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis.

Factors other than the underlying disease process and Glomerular hypertension that may cause progressive renal injury include the following: Systemic hypertension Acute insults from nephrotoxins or decreased perfusion Proteinuria Increased renal ammoniagenesis with interstitial injury Hyperlipidemia Hyperphosphatemia with calcium phosphate deposition Decreased levels of nitrous oxide Smoking Uncontrolled diabetes

Hyperkalemia
No hyperkelaemia if both aldosterone secretion and distal flow are maintained. Another defense against potassium retention in patients with chronic kidney disease is increased potassium excretion in the GI tract, which also is under control of aldosterone. Therefore, hyperkalemia usually develops when the GFR falls to less than 15-20 mL/min . potassium-rich diet or if serum aldosterone levels are low, use of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). acidemia or from lack of insulin

Metabolic acidosis
unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium. In chronic kidney disease stage 5, accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in anion gap.

Metabolic acidosis has been shown to have deleterious effects on protein balance Negative nitrogen balance Increased protein degradation Increased essential amino acid oxidation Reduced albumin synthesis Lack of adaptation to a low protein diet

Hence, metabolic acidosis is associated with proteinenergy malnutrition, loss of lean body mass, and muscle weakness. However, this leads to an increase in fibrosis and rapid progression of kidney disease. Metabolic acidosis is a factor in the development of renal osteodystrophy. Acidosis may interfere with vitamin D metabolism, and patients who are persistently more acidotic are more likely to have osteomalacia or low-turnover bone disease.

Salt and water handling abnormalities

Extracellular volume expansion and total-body volume overload results from failure of sodium and free water excretion.

This generally becomes clinically manifest when the GFR falls to less than 10-15 mL/min, when compensatory mechanisms have become exhausted.

Anemia
Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin No reticulocyte response occurs. EPO is produced by peritubular interstitial fibroblasts in the outer renal medulla and deep cortex of the kidney. Several mechanisms are implicated, including:
relative deficiency of erythropoietin diminished erythropoiesis due to toxic effects of uraemia on marrow precursor cells reduced red cell survival increased blood loss due to capillary fragility and poor platelet function reduced dietary intake and absorption and utilisation of iron.

Renal osteodystrophy
Combination of
Osteomalacia(Low ca and vit D) osteitis fibrosa ( high PTH) Osteoporosis ( co-exist with low or high turnover disease) osteosclerosis

Silent crippler
Calcium containing binders/Vitamin D/ Calcimimetics Low turn over PTH
<100pg/ml 150-300 pg/ml > 450 pg/ml

High turnover

Adynamic bone Osteomalacia

Normal bone turn over

Mild SHPT

Osteitis fibrosa

Spectrum of renal bone disease

C/F of renal osteodystrophy

Initially asymptomatic Later Bone pain, arthralgia, muscle weakness, pruritis(cutaneous calcium phosphate deposition), bony deformity. Fracture Adynamic bone dis-orderasymptomatic, high calcium CV risk soft tissue and cardiac calcification

 Treatment
Dietary phosphate restriction Phos Binders(Aluminium hydrochloride,CCPB,sevelamer Hcl and Lanthanum carbonate) Removal through adequate dialysis Vitamin D analogs Ca salt Calcimimetic agents

 Tertiary Hyperparathyroidism is essentially secondary hyperparathyroidism that is no longer responsive to medications. Also occurs after renal transplant, where hypertrophied glands continue to oversecrete PTH (set point alteration) May require surger

Diagnosis of CKD

eGFR if less ARF untill otherwise proved. USG S. Ca and S. phosphate S. creatinine persistently high

Halting progression of CKD

Progression of CKD is more often due to secondary haemodynamic and metabolic factors, than underlying disease actvity Factors
Non-modifiable- underlying cause, race Modifiable level of proteinuria, drugs, disease activity, hypovolaemia, dyslipidaemia, hyperphosphatemia,DM, Smoking

Management
CKD stage 1-3 Small portion to ESRD CV risk reduction should be emphasized Stage 1,2 at least annual f/u Stage 3 at least 6 monthly f/u- if Hb < 11 gm/dl and S. ferritin level < 100 mg/dl then start PO iron. Also do B12 and folate. Check S. ca and s. po4 and PTH annualy If PTH > 70 pg/ml - treat

When to refer to a nephrologist

eGFR < 30 ml/min/ 1.73 m square eGFR < 60 ml/min/1.73 m square and any of

Progressive fall ( >10 ml/min/m square in 2 successive years) Microscopic haematuria Proteinuria(ACR > 70mg/mmol) >15% decline in eGFR with commencement of an ACEI and ARB (? Renovascular disease) Possiblesystemic illness(SLE, Myeloma) PTH>70 pg/ml ACR >70gm/mmol Abnormal renal imaging Familly history of renal disease Suspected ARF

eGFR > 60 ml/min/ 1.73 m square and

Complications of CKD
Fluid overload Salt losing state Weight reduction < 0.5 to 1 kg/day Hyperkakaemia Acidosis
Bone Metabolism Effects on Resp. system Hyperkalaemia Ionized Ca Nutrition

Uraemia
Many remains un-identified Inflammation and oxidative stress,atherogenesis, immune system disruption and anaemia. Divided into small and middle molecules < 500 d and > 500 d Middle molecules include B-2 microglobulin 12000d Light chains Complement factor D cytokines

When to start dialysis ?

GFR < 15 with uraemic symptoms GFR < 10 with or without symptoms Refractory hyperkalaemia,acidosis,pulmonary edema,pericarditis,encephalopathyand neuropathy Pre-emptive transplantation is the treatment of choice. Consider when GFR is <20