Approach to renal stone disease by Residents in medical faculty

His kampong had a barber,

With sharp razor and a scissor,

Didn’t touch hair, but cut tumour.

‘Let me teach him artery and nerve down there’,

And make him clever’

But the barber, got a lot of fear,

Shaking hand couldn’t even touch hair.

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knowledge

Confident knowledge

Contents of your approach

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalceamia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical options, images

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Contents of your approach

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalceamia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical options, images

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Back to History

• The oldest urinary calculi on record from an Egyptian mummy dated about 4800 BC
• Hippocrates (2500 BC) first described renal colic due to stone - considered a classic description
• Galen (AD 130) first to associate stones with a metabolic origin
• Past 30 years, advances in Pathophysiology & molecular defects are unraveled
• New medicines and facilitated removal (lithotripsy and ESWL) developed

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Epidemiology of renal stone

• 95% are in upper urinary tract and in kidneys in developed country,
• Bladder stones are common in elderly with BPH and in children
• United States, 5 – 15% by the age of 70, man more than woman
• Worldwide, the lifetime stone: in men > 60 yrs varies from 1.5% in China, 5.4% in Japan, 8% in UK, 12% in Canada, and 20% in Saudi Arabia
• Recurrence: 14%, 35%, 52%, and 75% after 1, 5, 10, and 20 years
• 1% Hospitalisation for UTI, colic, haematuria; 1% ESRF

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Physicians approach to renal stone

• Most think it as Urologists issue (true in removal of stone)
• Nephrologist faculty deals Calcium-Vit D metabolism in Renal bone disease
• Internist thinks metabolic diseases
• Pathophysiology, medical treatment and preventive treatment, remain mostly medical faculty residents’ approach in the following points:
• Availing early diagnostic approach, identifying risk factors,
• Differentiating various causes and types of stone,
• Selection of specific drugs,
• Lifestyle changes
• Combined with approach of urological diagnosis and procedures.

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Another step is �Separation of Uncomplicated Stone Disease �from Complicated Stone Disease,

• Chronology of stone events, such as age of first stone passage and dates of further episodes, number and type of stones passed, spontaneous passage vs. need for surgical intervention;
• Family history of stones or personal history, for bone or gastrointestinal disease, gout, chronic urinary tract infection (UTI), or nephrocalcinosis;
• Stone-provoking medications; and
• Nutritional habits

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Contents……..

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Presentation�Acute renal colic

• Sudden onset of severe pain originating in the flank and radiating inferiorly and anteriorly;
• 50% of patients will also have nausea and vomiting.
• Patients with urinary calculi may report pain, infection, or hematuria.
• Patients with small, non-obstructing stones or those with staghorn calculi may
• Stones passed into bladder: Mostly asymptomatic; rarely, positional urinary retention asymptomatic or experience moderate and easily controlled symptoms

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Location Characteristics

• Stones at uretero-pelvic junction: deep flank pain without radiation
• Stones within ureter: colicky pain in the flank with radiation;
• Distal ureteral stones: Pain radiates into groin or perineum
• Stones passed into bladder: Mostly asymptomatic; rarely, positional urinary retention
• Renal and Staghorn calculi, ache , no pain, may have UTI
• Costovertebral angle tenderness, Tachycardia, Hypertension, haematuria

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Diagnosis

• Urinary sediment/dipstick test: for blood cells, test for bacteriuria (nitrite) and urine culture in case of a positive reaction
• FBC, UFEME, UECr, Ca, PO, iPTH, Uric acid, Cystine, S & U pH
• 24 hours Urine analysis
• Imaging
• X-ray KUB, Noncontrast abdomino-pelvic CT scan, IVU
• US, Tomogram, Retrograde Pyelogram, Ureteroscopy
• Renogram, for differential renal function.

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The European Association of Urology (EAU) recommendation

Diagnosis and interpretation

CLINICAL

• Renal Colic
• Urinary retention
• Passage of stone
• UTI recurrent
• Incidental
• X-ray KUB, IVU, US and CT scan

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BIOCHEMICAL

• Stone analysis
• UFEME Urinary microscopic sediments, Culture
• 24 hours urinary estimation of minerals, like
• Calcium, >4 mg/kg body weight/day
• Uric acid, >300 mg/L urine
• Oxalate, > 44 mg/day
• Cystine, 250 mg/g creatinine
• Blood analysis, Ca, Uric acid, iPTH, VitD

Urine pH

• pH<5.5 uric acid
• pH< 6.9, CaHPO₄ brushite stone
• pH>6.9, apatite Ca5(PO₄)₃ stone
• pH>7.2 Infection stone combination of struvite (MgNH₄PO₄) and carbonate-apatite (Ca10(PO₄)6CO₃ with urea-splitting organisms.

Radiology & Blood tests�interpretation

Radiopaque: (KUB)

• Calcium oxalate, calcium phosphate, and infection stones (due to their component of carbonate apatite).
• Cystine stones are also radiopaque, though less dense.

Radiolucent

• uric acid, 2,8-dihydroxyadenine, triamterene, xanthine and silica.

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Blood Tests

• To identify primary hyperparathyroidism high serum calcium concentration, SAP, iPTH),
• Gouty diathesis (hyperuricemia),
• Distal RTA (low pH, hypokalemia, low CO₂, urine pH, and hyperchloridemia),
• Hypercalciuria
• Renal function

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Contents………

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Pathology�Stone composition

• Matrix (5%), protein support, in concentric layers or radial striations in the stone, holding Minerals (95%), mostly in crystalline form
• Stone analysis: Infrared spectroscopy and X-ray diffraction crystallography
• Three basic types of minerals: Majority of stones are a mixture of 2 or more minerals:
• Calcareous with Ca Oxalate mainly 75%,
• Non-calcareous remainings:
• Uric acid 5-10%,
• Struvite Mg NH4PO4, 5-10%, also called Infectious stone as develop from UTI with urea splitting organisms.
• Cystine stone
• Miscelleeous

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Stone composition

• Matrix (5%), protein support, in concentric layers or radial striations holding:

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• Minerals (95%), mostly in crystalline form

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Stone matrix is composed of about

64% protein,

12% organic ash,

10% bound water,

9% non-amino sugars, and

5% glucosamine.

Stone types and composition, nomenclature

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Contents…….

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Process of stone formation

• Three theories:
• Precipitation> from super-saturation of urine > crystallization > Nidus formation > Crystal growth > Stone formation
• Inhibitory theory and promoter theory
• Matrix theory, an organic matrix similar to mineralization of bone.

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STAGES PROCESS DETERMINANTS

SUPERSATURATION MATRIX FORMATION Ionic Concentration

pH of urine

NUCLEATION Urinary Inhibitors

NIDUS Promoters

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Crystal growth Super-saturation

STONE Crystal aggregation Inhibitors

Wall Cell adhesion Promoters

Process of stone formation

• Conditions for Nucleation:
• Increase in concentration,
• Decrease in ligands (citrate for calcium solubility),
• Change in pH
• <5.5 for uric acid,
• >7 for CaPO4 & MgNH4-PO4
• Inhibitors of crystalisation

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Deficiency of Inhibitors:

Inhibitors:

I) Low-molecular-wt:

Citrate, Magnesium, Pyrophosphate, Trace metals

II) High-molecular-wt:

Glycosaminoglycans, Nephrocalcin, Prothrombin F1 peptide, Uropontin,Tamm-Horsfall protein, Uronic acid rich protein

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Risk factors

• Anatomical abnormalities:
• Ectopic,, horseshoe kidney,
• stenosis at all levels
• polycystic, Medullary sponge kidney
• Functional abnormalities:
• Increased intake and absorption
• Increased production
• Low urine volume and stasis

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• Metabolic abnormalities
• Distal renal tubular acidosis
• (RTA) causing hypercalciuria and hypocitraturia),
• Primary metabolic abnormality
• Hyperoxaluria
• Hypercalciuria
• Hyperuricosuria
• Cystinuria

Risk factors…

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Hypo-citraturia-�(Citrate- a common inhibitor)

• Citric acid is a tricarboxylic acid is a key component of the tricarboxylic acid cycle (Krebs’ cycle), in which ATP is produced from glucose
• Citrate represents the most abundant of the organic anions and acids present in the urine and plays an important role as an inhibitor of the crystallization of calcium salts.
• Citrate forms a complex with calcium, causing a reduction in the ionic calcium concentration inhibiting cal stone formation.

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Low Citrate level (Inhibitor of stone)

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Low Citrate develops:

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I) Acidosis

1. Distal renal tubular acidosis

2. Chronic diarrheal syndrome

3. Hypokalemia

4. Strenuous physical exercise

5. High sodium or meat intake

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II) Urinary tract infection

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III) Idiopathic

Contents……..

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturia (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Calcium Oxalate stones

• Oxalic acid is a two-carbon dicarboxylic acid, (HOOC-COOH)
• A toxic substance.
• Forms crystals with Calcium, magnesium, ferrous iron and zinc.
• Crystallizes readily.
• Ca oxalate is 400 times less soluble than urate.

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Hyperoxaluria

• Dietary hyperoxaluria
• Enteric hyperoxaluria

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• Primary Hyperoxaluria

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• Drug induced hyperoxaluria, ethylene and methoxyflurane

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Dietary hyper-oxaluria

• Widely consumed foods are rich in oxalic acid:
• Vegetables, nuts, cocoa, tea and fruits high in vit-C.
• Western diets:
• Spinach, rhubarb, beets, nuts, chocolate, tea, wheat bran, and strawberries.

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• May lead to hyperoxaluria

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Enteric hyperoxaluria

• surgical interventions in the gastrointestinal tract and including medical diseases of the gastrointestinal tract

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Endogenous - Hepatic production

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Pyridoxine –

Inhibiting endogenous

oxalate production

A co-factor for enzyme

AGT (Alanine Glycoxylate

aminotransferase) which

converts Glycoxylate to

Glycine.

In the absence, it is

converted to Oxalate

instead.

Pyridoxine

+ AGT

Ascorbic acid

Primary hyperoxaluria

1. Autosomal recessive, endogenous over production of oxalate
2. Nephrolithiasis, nephrocalcinosis, end-stage renal failure are the clinical hallmarks
3. Managed by Pyridoxine, renal transplantation

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Oxalate, Hyperoxaluria

• Risk of kidney stone, increases

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Obvious hyperoxaluria

• Randall’s plaque (apatite collections
• in the interstitium of the papillae)
• Nephrocalcinosis
• Renal stone and Hydronephrosis

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Management of oxalate induced nephropathy

• Diet low in oxalate, fluid intake exceeding 1.5 L per m2 body surface area per day,
• Oxalate chelation by CaCO3 or citrate for chelating food oxalate
• Oxalolytic probiotics, break down food oxalate
• Load reduction by Pyridoxine through hepatic oxalate production inhibition

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Uric acid (C₃H₄N₄O₃),

Hyperuricosuria

• Final breakdown product of purine.
• Xanthine oxidase,
• primarily liver and small intestine.
• Urates, the ionized forms of uric acid,
• predominate in plasma, extracellular fluid, and synovial fluid,
• 98 percent existing as monosodium urate at pH 7.4.
• easily filtered by kidney and dialyzed from plasma.

Nuclic (Purine) acid synthesis

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XOI

XOI : Xanthine oxidase inhibitor (Allopurinol)

XOI

Hyperuricaemia and Hyperuricosuria

• Hyperuricemia > 420 umol/L (7.0 mg/dL)
• Solubility limits of monosodium urate in plasma, 415 umol/L (6.8 mg/dL).
• 2.0 - 13.2% in adults.
• Hypruricosuria; > 750 - 800mg/day in urine (in acidic urine >300 mg/day.
• Nephrolithiasis.
• Chronic uric acid nephropathy
• Acute uric acid nephropathy

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Allopurinol

• A substrate and competitive inhibitor of xanthine oxidase
• Oxypurinol, the major metabolite of allopurinol
• Indicated for the following:
• patients with nephrolithiasis of any type plus urinary uric acid excretion greater than 3.6 mmol/d (600 mg/d);
• patients with renal calculi composed of 2,8-dihydroxyadenine; and
• patients with, or at risk for, acute uric acid nephropathy.

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Allopurinol

• Decreases the serum urate concentration and the urinary excretion
• Effective dose is 300 mg/d.
• Potential drug interactions: 6-mercaptopurine and azathioprine
• Cyclophosphamide toxicity also may be enhanced by concomitant use.

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Allopurinol side effects

• Allergy: HLA-B*58-01 association
• skin rash, hypersensitivity vasculitis, and death.
• gastrointestinal distress, diarrhea, and
• headache, alopecia, fever, lymphadenopathy,
• bone marrow suppression,
• hepatic toxicity,
• interstitial nephritis, renal failure,

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Contents

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Hypercalciuria

• Most common cause (60%)
• (about 1 g of calcium intake) as urinary calcium excretion in 24 hours 4 mg/kg body
• Absortive hyprecalciuria most common
• Hyper-parathyroidism (Primary) , - patients are hypercalcaemic.
• Renal hypercalciuria, - patients are normocalcaemic
• Primary (idiopathic) hypercalciuria, - patients are normocalcaemic

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Parathyroid Physiology�Normal situation

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Parathyroid

Kidney

Calcium

Intestine

Bone

1,25(OH) ₂D

PTH

-

-

+

+

Skin

Liver

7-dehydro-

cholesterol

Pro-

Vitamin D

Vitamin D

DBP

1-α-OH

UV light

25-(OH)D

Hypercalciuria and nephrolithiasis

• Absortive hypercalciuria, increased Vitamin D due to increased VDR in intestine
• Hypervitaminosis D
• Primary hyperparathyroidism.
• Thiazide diuretics inhibit renal excretion of Calicium, thus causes hypercalcaemia and low urinary Calcium, used in idiopathic hypercalciuria.

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Hypomagnesiuria�

• Magnesium inhibits stone formation by binding oxalate, Thus, calcium oxalate crystallization could be enhanced in the setting of hypomagnesiuria.
• Hypomagnesiuria occurs in chronic diarrheal syndrome from malabsorption of magnesium, thus increasing the risk for nephrolithiasis in patients with bowel disease

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Contents

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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High Urinary pH

• At high pH < 6.9, brushite (CaHPO4 · 2H2O) is the predominant phase of calcium hydrozen phosphate salts
• Higher pH (>7.2) in UTI with urea splitting organisms
• Favours formation of Calcium-apatite Ca5(PO4)3(OH) stones
• Same happens in distal RTA.

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Infection stones

• Urine infected with urea-splitting organisms and are composed of a combination of struvite (MgNH4PO4 · 6H2O) and carbonate-apatite (Ca10(PO4)6CO3).
• The action of urease within the urinary tract produces high levels of Ammonium, carbonate, and urinary pH > 7.2.
• The resulting alkalinity of urine increases the amount of trivalent phosphate, as already mentioned.
• Thus, the urinary environment becomes supersaturated with struvite and carbonate apatite, leading to the crystallization.

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Chronic UTI..

• Proteus species are responsible for the majority of infection that cause these stones in all age ranges.
• Other common organisms that produce urease areHaemophilus influenzae, Staphylococcus aureus, Yersinia enterocolitica, and Ureaplasma urealyticum (this last requires special culture techniques for its detection).
• Escherichia coli does not produce urease and therefore is not responsible for the formation of infection stones

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Cystinuria

• Cystinuria is an autosomal recessive disease
• increased urinary excretion of the dibasic amino acids cystine, arginine, lysine, and ornithine.
• Only cystine is insoluble enough to precipitate in physiological settings.

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Contents

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Medical Management

• primary objective

-prevention of recurrent stone formation.

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Pharmacotherapy and supportive care�

• IV hydration
• NSAIDs and paracetamol
• KIV narcotic analgesics (eg, codeine, morphine sulfate)
• Alpha blockers (eg, tamsulosin, terazosin) to facilitate stone passage
• Antiemetics (eg, metoclopramide, ondansetron)
• Antibiotics (eg, ampicillin, gentamicin, trimethoprim-sulfamethoxazole, ciprofloxacin)

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Conservative�Approach�based on urinary findings.

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Conservative management..

• Dietary modification
• Fluid intake to increase 3l, to maintain UO of >2l (55% reduction in 5 yrs)
• Avoidance of Oxalate rich food, avoid vit c, excessive tea
• Calcium intake to be restricted dietary product, spinach, excellive milk
• Uric acid restriction by meat restriction
• Look for chronic uti, bowel disease, hyperparathyroidism

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Stone-provoking Medications to avoid

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Disease specific agents

• Uricosuric agents (eg, allopurinol)
• Alkalinizing agents (eg, potassium citrate, sodium bicarbonate) - for uric acid and cysteine calculi
• Thiazide diuretics - help treat hypercalcicuria
• Pyridoxine, Orophosphate, Calcium Citrate for Oxalate tone.

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Contents

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option

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Surgical options�Stones that are 7 mm and larger are unlikely to pass spontaneously and require some type of surgical procedure, such as the following:�

• Stent placement
• Percutaneous nephrostomy
• Extracorporeal shockwave lithotripsy (ESWL)
• Ureteroscopy
• Percutaneous nephrostolithotomy (PCNL) or mini PNCL
• Open nephrostomy - largely supplanted by less-invasive techniques
• Anatrophic nephrolithotomy - for large. complex staghorn calculi that cannot be cleared by an acceptable number of PCNLs; typically done via laparoscopic or robotic approach

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Contents

• Back to history, -Epidemiology, -Physicians approach to renal stone
• Presentation, Diagnosis, uncomplicated stone and Complicated stone disease
• Pathology - Stone composition, types, minerals
• Process of stone formation, Risk factors, -Inhibitor of stone, hypocitraturi (inhibitor deficiency)
• Types of stone diseases – Oxalate stone, Uric acid stone,
• Hypercalciuria, Hypercalcaemia, hypomagnesiuria,
• Infection stone, high urine pH, and Cystine stone
• Medical management: Diagnosis and Algorithm for diagnosis, Conservative management
• Surgical option
• Images

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Images�Plain KUB

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• Allows for the evaluation of urinary tract stones
• 90% stones are radio-opaque.
• Visibility of stones depends on the degree of opacity, sizes and positions relative to other abdominal structures.
• stone needs to be at least 2mm to be visible on KUB.
• Poor sensitivity for ureteral stones

US kidneys

Normal kidney

CKD

US kidneys

• Detects uric-acid as well as calcium stones.
• Stones are seen as highly echogenic foci and distal acoustic shadowing
• Not always possible to distinguish small stones from arterial calcifications

Kidney stone

CKD

Thank you

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