MEDICAL MANAGEMENT OF RENAL STONES

KIDNEY STONES Introduction This disease is not transmittable. Kidney stones can develop when certain chemicals in urine form crystals that stick together. Stones may also develop from a persistent kidney infection. Drinking small amounts of fluids. More frequent in hot weather

SYMPTOMS Pain in the lower back part or in the lower abdomen, which might move to the groin. Pain may last from hours to minutes. Nausea, vomiting Blood in urine Burning during urination, foul smell in urine, chills, weakness and fevers for urinary tract infection.

EPIDEMIOLOGY This disease can be found anywhere. This disease can strike on any age group.

COMPARATIVE INCIDENCES OF FORMS OF URINARY LITHIASIS Stone analysis in Percentage Form of Lithiasis India USA Japan UK Pure Calcium Oxalate 86.1 33 17.4 39.4 Mixed Calcium Oxalate and 4.9 34 50.8 20.2 Phosphate Magnesium Ammonium 2.7 15 17.4 15.4 Phosphate (Struvite ) Uric Acid 1.2 8.0 4.4 8.0 Cystine 0.4 3.0 1.0 2.8

Cause of Stone Disease Supersaturation of urine is the key to stone formation Intermittent supersaturation - Dehydration Crystal aggregation Anatomic Abnormailities – PUJ , MSK Bacterial Infection* Defects in transport of Calcium and Oxalate by Renal epithelia *E.Coli infection increases matrix content in urine . Proteus makes urine alkaline

Inhibitors, Promoters of Stone Formation Inhibits crystal Growth - Citrate – complexes with Ca Magnesium – complexes with oxalates Pyrophosphate - complexes with Ca Zinc Inhibits crystal Aggregation Glycosaminoglycans Nephrocalcin PROMOTERS Bacterial Infection Matrix Anatomic Abnormalities – PUJ obst., MSK Altered Ca and oxalate transport in renal epithelia Prolonged immobilisation Increased uric acid levels i.e taking increased purine subs– promotes crystalisation of Ca and oxalate ?? Nanobacteria – seen in 97% of renal stones

SOME DISEASES ASSOCIATED WITH HYPERCALCAEMIA & HYPERCALCIURIA Hyperparathyroidism Leukemia Sarcoidosis Lymphoma Multiple myeloma Myxedema Hyperthyroidism Adrenal Insufficiency Metastatic Malig. Neoplasm's Vit. D Intoxication

TYPES OF KIDNEY / URETER STONES OXALATE (CALCIUM OXALATE) PHOSPHATE URIC ACID & URATE CYSTINE

Uncommon Stones XANTHINE STONES – Autosomal Recessive – Def. of Xanthine Oxidase leading to Xanthinuria DIHYDROXYADENINE STONE – Def. of enzyme adenine phospo ribosyl transferase SlLICATE STONES – Rare in humans - excess intake of Antacid with Mg Trisilicate ( Mostly in cattle due to ingestion of sand ) MATRIX - Infection by Proteus - Radiolucent (all calculi have some amt ( 3%) of matrix but matrix calculus has 65% Matrix content in calculi)

Uncommon Stones TRIAMTERENE – Anti-hypertensive used with hydroclorothiazide – spares potassium. Mostly found as a nucleus in Ca-oxalate or uric acid calculus Indinavir Stones - Drug to treat AIDS (4 to13%) Ephedrine or Guifenesin – Cough medicine - Radiolucent

Stones – Chemical Constituents Whewelite – Calcium Oxalate Monohydrate – CaC2O4-H2O Weddelite - Calcium Oxalate dihydrate – CaC2O4-2H2O Brushite – Calcium Hydrogen phosphate dihydrate – CaHPO4 2H2O Whitlockite - TriCalcium Phosphate – Ca2(PO4)2 Struvite – Magnesium Ammonium hexahydrate – MgNH4PO4-6H2O

DD of Radiolucent filling defect on IVU Know For Brownie Points Xanthine Calculus Hydroxyadenine Calculus Ephedrine Calculus Infection due to gas forming Org. Fungal Ball Tuberculoma Malacoplakia Hypertrophied Papilla Renal pseudo-tumour Must Know Uric Acid Calculus Matrix Calculus Sloughed Papilla Blood Clots TCC Renal Cysts Vascular Lesions

OXALATE (CALCIUM OXALATE) ALSO CALLED MULBERRY STONE COVERED WITH SHARP PROJECTIONS SHARP ® MAKES KIDNEY BLEED (HAEMATURIA) VERY HARD RADIO - OPAQUE Under microscope looks like Hourglass or Dumbbell shape if monohydrate and Like an Envelope if Dihydrate

PHOSPHATE STONE USUALLY ® CALCIUM PHOSPHATE SOMETIMES ® CALCIUM MAGNESIUM AMMONIUM PHOSPHATE OR TRIPLE PHOSPHATE SMOOTH ® MINIMUM SYMPTOMS DIRTY WHITE RADIO - OPAQUE Calcium Phosphate also called ‘Brushite’ appears ‘needle-shaped’ under the microscope

PHOSPHATE STONES IN ALKALINE URINE ¯ ENLARGES RAPIDLY ¯ TAKE SHAPE OF CALYCES ¯ STAGHORN ® Struvite can form ‘stag-horn’ and appear like coffin lid under microscope

CALCIUM PHOSPHATE STONES Hyperparathyroidism Ca P Renal Tubular Acidosis K CO2 Medullary Sponge Kidney - PTH Hormone Promotes renal production of 1-25-dihyroxycholecalciferol – active Vit.D and also increases absorption of Calcium and decreases Phosphorus absorption from Kidneys

URIC ACID & URATE STONE HARD & SMOOTH MULTIPLE YELLOW OR RED-BROWN RADIO - LUCENT (USE ULTRASOUND) Under microscope appear like irregular plates or rosettes pKa of uric acid 5.75 – at this pH 50% of uric acid insoluble. If pH falls further - uric acid more insoluble

CYSTINE STONE AUTOSOMAL RECESIVE DISORDER USUALLY IN YOUNG GIRLS DUE TO CYSTINURIA - CYSTINE NOT ABSORBED BY TUBULES MULTIPLE SOFT OR HARD – can form stag-horns PINK OR YELLOW - RADIO-OPAQUE Under microscope appears like hexagonal or benzene ring – ask for first morning sample

CYSTINE STONE - Management High Fluid Intake and Alkalanise Urine – dissolve most of the smaller cystine stones D-Pencillamine or MPG (Mercaptopropionylglycine) binds to cystine that is soluble in urine Side effects of Pencillamine restricts it use – Allergic rashes, GI problems- Nausea, Vomiting, Diarrhoea MPG better tolerated Large obstructive stones – Surgery required pKa of cystine is 8.3, hence alkalinisisation above pH7.5 helps to dissolve the stones Cyanide Nitroprusside Calorimeteric Test for detecting Cystinuria. If positive do amino acid chromatography

Surgical Conditions and Stone Disease Regional ileitis and Ileal Bypass Surgery for Obesity can lead to increased oxalate absorption and stone disease Ileostomies, in Chr. Diarrhoea with Bicarbonate loss – systemic acidosis and acidic urine – increases risk of Uric Acid stones

HISTORY A. IS PATIENT DRINKING ENOUGH ? B. PROFESSION C. ENQUIRE ABOUT UTI - STONES D. FAMILY HISTORY E. LONG ILLNESS - BEDRIDDEN - STONES

MANAGEMENT OF STONES HISTORY : A. FIND OUT IF DRINKING ENOUGH LIQUIDS (NOT DRINKING ENOUGH IMPORTANT CAUSE OF STONE FORMATION & GROWTH) Urinary supersaturation of salts in concentrated urine Atleast drink 3 lts to avoid stone formation

HISTORY (Cont...) B. ASK ABOUT THEIR PROFESSION DEHYDRATION - STONES CAN FORM e.g. MARATHON, NEAR A FURNACE, BRICK - LAYER, LABOURERS & WEAVERS TRUCK & BUS DRIVERS

HISTORY (Cont...) C. ENQUIRE ABOUT UTI ® STONES D. FAMILY HISTORY E. LONG ILLNESS ® BEDRIDDEN ® STONES Zero Gravity state – astronauts on long space flights more prone to stones

CLINICAL FEATURES 1. PAIN IN 75 % OF THE CASES “RENAL COLIC” IF SEVERE AND ACUTE A) KIDNEY STONE FIXED PAIN IN THE LOIN B) URETERIC STONE PAIN RADIATES ® LOIN TO GROIN Both Stomach & Kidney supplied by celiac ganglion hence nausea & vomiting common in renal colic

CLINICAL FEATURES (Contd....) 2) HAEMATURIA CAN BE FRANK OR ONLY FOUND ON DIP - STICK OR LAB. 3) PYURIA - IF INFECTION, CAN HAVE PUS IN URINE

ON EXAMINATION 1. ACUTE PRESENTATION ABDOMEN TENSE AND RIGID TENDERNESS PRESENT IN THE LOIN 2. IN ROUTINE PRESENTATION NO FINDINGS IN ABDOMEN

INVESTIGATIONS 1. FULL BLOOD COUNT TO CHECK FOR ANAEMIA, IF GOING FOR SURGERY 2. SERUM ELECTROLYTES PLUS UREA / CREATININE / CALCIUM / URIC ACID / PHOSPHATE

INVESTIGATIONS (Cont...) 3. 24-HOURS URINE FOR ELECTROLYTES (Only if recurrent stone former) CALCIUM / OXALATE / URIC ACID / CYSTINE / CITRATE

INVESTIGATIONS (Cont...) 4. PLAIN KUB X-RAY OF ABDOMEN (Mandatory) 5. IVU (INTRA VENOUS UROGRAM) OR IVP 6. ULTRASOUND (Mandatory)

INVESTIGATIONS IVU OR IVP - Not Mandatory 1 in 40,000 patients die due to anaphylactic reaction to contrast Useful for radio-lucent stones & to detect Congenital Anomalies in Urinary tracts

INVESTIGATIONS (Cont...) 7. CT – TO LOOK AT UNUSUAL ANATOMY OF THE KIDNEY To differentiate cause of acute colic – stone or anuria suspected due to stone disease 8. DMSA OR DTPA OR MAG3 RENOGRAM - TO STUDY FUNCTION OF EACH KIDNEY.

Bilateral Ureteric Calculus in a patient presenting with Anuria Helical or Spiral CT provides 3D reconstruction. Helical refers to path the X ray follows on Gantry. These are rapidly performed and do not require contrast agents for reconstruction.

MANAGEMENT OF UROLITHIASIS Non-invasive approach to urinary calculus -HALLMARK for last 20 yrs. Lithotripters – 1.Extra Corporeal Shock wave 2.Intra Corporeal Better fiber optics – Miniaturisation of Telescopes Accessories - Innovative variety

Diet & Fluid Advice High Fluid Intake Restrict Salt (Na) Oxalate Restrict Avoid high intake of Purine food Increased citrus fruits may help If hypercalciuria restrict Ca intake Role of Potassium Citrate in preventing Cal Oxalate stone ds – KCit lowers urinary calcium whereas Na Citrate does not lower Calcium due to Sodium load

LIQUIDS Moderate Amounts : High Amounts : Apple Juice Cocoa Beer Fresh Tea Coffee Cola FOODS : Almonds, Asparagus, Cashew Nuts, Currants, Greens, Plums, Raspberries, Spinach

Principles of Medical Management Monitor stone burden with periodic KUB Instruct patient on adequate water consumption ( enough to produce 2L of urine in 24 hrs.) Instruct in low oxalate and modified calcium diet If hypercalcuric, treat with hydrochlorothiazide (monitor urinary Ca) Not all patients with renal stones require treatment. If the stone is metabolically inactive (has remained unchanged in location, size and number, not produced any symptoms) then it may be reasonable to observe. Observation should include: a periodic KUB to determine if the stone is changing, urine culture to detect presence of unsuspected infection and continuous exhortations on the part of the MD to encourage adequate water intake and adherence to a low oxalate and moderate calcium diet. The patient needs to consume enough water to produce 2,000cc’s of urine in a 24 hour period. It has been shown that at this rate of urine production the occurrence of ss is reduced and that the ensuing dieresis will “flush out” intraductal crystalline clumps. Obviously this will require far more water consumption i the hot weather when there is increased extra-renal fluid loss. Patient who are hypercalciuric should first be tried on a low calcium diet. There are 2 types of hypercalcuria type 1 where the hypercalcuria is refractory to dietary restriction of calcium and type 2 where the hypercalcuria can be controlled. If the patient’s hypercalcuria can not be controlled by dietary restriction it is reasonable to try hydrochlorothiazide at a dose of 25 mgs BID. After 3-4weeks of HCTZ the 24 hour Ca should be repeated and if still high increase the dose of HCTZ. Potassium citrate is also helpful in inhibiting the stone formation process by forming a chelate with Ca and removing it from being available to bind with oxalate. K citrate also has the advantage of providing K+ in patients receiving HCTZ.

Principles of Medical Management 2 If hyperuricosuric allopurinol if serum uric acid elevated alkalinize urine if serum level is normal If active Ca stone former not aided by diet, HCTZ added to K-citrate If magnesium ammonium phosphate stone, after reduction of burden treat aggressively with antibiotics The patient with hyperuricosuria can be treated with allopurinol which will lower the serum and urinary uric acid level. Also very effective control of uric acid stones can be achieved with oral alkalization agents. The simplest one to use is sodium bicarbonate. Sodium bicarbonate is available in 600mg size tablets. Patients are instructed in the use of pH paper and measure their urine pH at each voiding. The untreated uric acid stone former will always have a low urinary pH in the range of 5. Patients should be started off with a bicarbonate dose of 1.2 to 1.8 gms Q 4 hours. The goal is to get the urine pH to 7.0. If the pH is 6 then the next bicarbonate dose should be increased by i tablet (600mgs). If the pH is higher than 7.0 the bicarbonate dose should be decreased by 600mgs. Maintaining the urine pH at 7.0 will dissolve most uric acid stones and prevent the formation of new ones. Patients with struvite (magnesium ammonium phosphate) stones often have an associated urea splitting infection. It is important after reducing the stone burden to treat these infections very aggressively otherwise they will continue to produce a very alkaline pH and cause further struvite stone formation.

Anatomic Evaluation Necessary to decide on how to best treat size and location of stone number of stones anatomy of kidney, ureter is stone overlying bone “condition” of involved kidney The patient with chronic or recurrent stone formation should have evaluation of the anatomy of their urinary tract since there may be an underlying anatomic abnormality predisposing to stone formation. Examples of these would be: ureteropelvic junction obstruction, horseshoe kidney, ectopic kidney and malrotated kidney. If there is normal renal function then the most helpful study is the IVU. This will provide the needed information about the renal anatomy and will also delineate the size, location and presence of obstruction.

Principles of Stone Prevention Prevent supersaturation water! water and more water enough to make 2L of urine per day prevent solute overload by low oxalate and moderate Ca intake and treatment of hypercalcuria replace “solubilizers” i.e... citrate manipulate pH in case of uric acid and cystine Flush! forced water intake after any dehydration From the information presented above you can see that the mainstay to stone prevention is to prevent urinary ss by consuming enough water to produce 2,000ccs of urine per day. Prevention of solute overload by controlling the oxalate intake. Calcium intake should not be eliminated altogether but should be limited to about the equivalent of no more than 240ccs of milk per day. In the case of uric acid stone formers one should avoid eating large amounts of red meat “organ” meats which contain large amounts of purines. The replacement of solubilizers such as citrate can be helpful and should be tried in the unresponsive Ca stone former who is failing treatment with HCTZ. Stone patients must continuously be reminded that even though they may have been successfully managed for a period of months or years that it is still important for them to remain on treatment indefinitely since the causes for their stone problem have not been removed.

Urine citrate Hypocitriuria is one of the most remarkable Feature of renal tubular acidosis and kidney stone Formation Hypocitriuria is a frequent finding in individuals with Recurrent stone formation. Presence of citrate in urine is an inhibitor of stone formation.

Emergency Department Care Intravenous access - for analgesics and antiemetics Intravenous hydration is controversial. May hasten passage of the stone Others feel exacerbates the pain of renal colic IV hydration should be given in dehydration or with a borderline serum creatinine level who must undergo IVP Strain urine for stone collection Ref: J Endourol. Oct 2006;20(10):713-6

ED Care – Analgesics Antiemetics Analgesia should be provided promptly. The pain of renal colic is mediated by PGE2. NSAIDs inhibit formation of this mediator NSAIDs have been proven in multiple studies to be as effective as opioid analgesics, with fewer adverse effect Opioid analgesics can be added in cases of incomplete pain control Antiemetics should be administered as needed Ref: Arch Intern Med. Jun 27 1994;154(12):1381-7 Am J Emerg Med. Jan 1999;17(1):6-10

ED Care - Expulsive therapy Multiple prospective randomized controlled studies in the urology literature have demonstrated that patients treated with oral alpha-blockers have an increased rate of spontaneous stone passage and a decreased time to stone passage The best studied of these is tamsulosin, 0.4 mg administered daily Ref: J Urol. Dec 2003;170(6 Pt 1):2202-5 J Urol. Jul 2005;174(1):167-72 J Urol. Aug 2004;172(2):568-71

ED Care - Expulsive therapy CCBs in combination with oral steroids have also proven efficacious in multiple studies. The most common regimen is 30-mg slow-release nifedipine daily plus oral corticosteroid such as prednisolone A systematic review found that medical expulsive therapy using either alpha antagonists or CCBs augmented the stone expulsion rate for moderately sized distal ureteral stones Ref: Ann Emerg Med. Nov 2007;50(5):552-63

ED Care - Expulsive therapy A systematic review found that medical expulsive therapy with alpha antagonists for 28 days increased the rate and decreased the time to stone passage; decreased the rates of hospitalization and ureteroscopy Ref: Ann Pharmacother. Jul-Aug 2006;40(7-8):1361-8

Ca-oxalate, ca-phosphate, and ca-urate are associated with: Hyperparathyroidism - Treated surgically or with orthophosphates if the patient is not a surgical candidate Increased gut absorption of calcium - The most common identifiable cause of hypercalciuria, treated with calcium binders or thiazides plus potassium citrate

Ca-oxalate, ca-phosphate, and ca-urate are associated with: Renal calcium leak - Treated with thiazide diuretics Renal phosphate leak - Treated with oral phosphate supplements Hyperuricosuria - Treated with allopurinol, low purine diet, or alkalinizing agents such as potassium citrate

Ca-oxalate, ca-phosphate, and ca-urate are associated with: Hyperoxaluria - Treated with dietary oxalate restriction, oxalate binders, vitamin B-6, or orthophosphates Hypocitraturia - Treated with potassium citrate Hypomagnesuria - Treated with magnesium supplements

Struvite (magnesium ammonium phosphate) stones Struvite stones are associated with chronic UTI with gram-negative rods capable of splitting urea into ammonium, which combines with phosphate and magnesium Underlying anatomical abnormalities that predispose patients to recurrent kidney infections should be sought and corrected

Struvite (magnesium ammonium phosphate) stones Usual organisms include Proteus, Pseudomonas, and Klebsiella species Escherichia coli is not capable of splitting urea and, therefore, is not associated with struvite stones UTI does not resolve until stone is removed entirely Urine pH is typically greater than 7

Uric acid stones Associated with urine pH less than 5.5, high purine intake (eg, organ meats, legumes, fish, meat extracts, gravies), or malignancy Approximately 25% of patients with uric acid stone have gout - serum and 24-hour urine sample should be sent for creatinine and uric acid determination If serum or urinary uric acid is elevated, the patient may be treated with allopurinol 300 mg daily Patients with normal serum or urinary uric acid are best managed by alkali therapy alone

Cystine stones Treated with low-methionine diet (unpleasant), binders such as penicillamine or a-mercaptopropionylglycine, large urinary volumes, or alkalinizing agents A 24-hour quantitative urinary cystine determination helps to titrate the dose of drug therapy to achieve a urinary cystine concentration of less than 300 mg/L

Drug-induced stone disease A number of medications or their metabolites can precipitate in urine causing stone formation These include indinavir; atazanavir; guaifenesin; triamterene; silicate (overuse of antacids containing magnesium silicate); and sulfa drugs including sulfasalazine, sulfadiazine, acetylsulfamethoxazole, acetylsulfasoxazole, and acetylsulfaguanidine Ref: Urology. Oct 2003;62(4):748 Urol Clin North Am. Feb 2003;30(1):123-31 Urology. Jan 2004;63(1):175-6

Potassium-magnesium-citrate Potassium citrate reduces urinary saturation of calcium by complexing with calcium in urine and thus reduces urinary calcium Citrate also inhibits spontaneous nucleation of calcium oxalate and calcium phosphate Due to its alkalinising effect it increases dissolution of uric acid and thus reduce uric acid stone formation

Magnesium It forms complex with oxalate and reduces supersaturation of urine with calcium oxalate It increases pH of urine and thus inhibit stone Formation Magnesium has direct inhibitory influence on Calcium phosphate crystal growth. Magnesium also prevents intestinal absorption of Oxalate 1 1. Am J Ther,2006 Mar-Apr ; 13(2) : 101-8

CONCLUSION As compared to potassium citrate , Potssium –magnesium citrate cause more Rise in urinary pH Rise in urinary citrate level Rise in urinary magnesium level Reduction in undissociated uric acid level Equally effective in correcting thiazide induced hypokalemia

Potassium magnesium citrate based medical prophylaxis is effective for preventing recurrence of urinary stones like calcium oxalate, hypercalciuria, hyperuricosuria and hypocitriuria Regular prophylaxis effectively prevent stone recurrence regardless of stone composition, metabolic abnormalities and stone –free status.

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