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Te SECTION Nephrology SECTION EDITOR Vivekanand Jha Nephrolithiasis and Urinary Tract le Obstruction Jacob George NEPHROLITHIASIS Introduction Nephrolithiasis refers to stones within the renal tubules or collecting system. While nephrolithiasis can be asymptomatic, they occasionally present with excruciating pain and can even be a cause of renal failure. Epidemiology Nephrolithiasis is common in industrialized nations with some areas considered as “stone belts” due to environmental reasons including composition of drinking water, The Persian Gulf area, North Western part of India, etc., have a higher prevalence of stones. Men are more prone. Etiopathogenesis Supersaturation of urine with substances such as calcium, oxalate, and uric acid can result in stone formation. Crystal aggregates can anchor to certain sites of the uroepithelium like Randalls plaque and increase in size. Risk Factors for Nephrolithiasis Various dietary and other conditions affecting urinary composition can predispose to stone formation (Box 1). There is a 10-30% risk of stones recurring by 3-5 years and as high as 50% by 10 years. Family history may be positive in certain conditions such as oxalosis, cystinuria, and inherited forms of hypercalciuria. Persistent acidic urine can promote Uric Acid Stones This accounts for around 8% of stones and is associated with persistently acidic urine (pH < 5.5), conditions increasing uric acid production, and situations where there is increased urinary uric acid excretion. Struvite Stones They are less common (1% of all calculi). They are branched stones that fill all or part of the renal pelvis and composed of magnesium ammonium phosphate (triple phosphate) (Fig. 1). This can lead to sepsis, deterioration of renal functions, and even end stage renal disease. Diseases associated with calcium stones. + Hyperparathyroidism + Distal renal tubular acidosis + Medullary sponge kidney + Inflammatory bowel disease FIGURE 1: Plain X-ray kidney, ureter, and bladder (KUB) showing bilateral staghorn calculi. Cystine Stones This is seen in a genetic disorder where there is a tubular defect in transport of dibasic amino acids such as cystine, ornithine, arginine, and lysine resulting in cystinuria. CLINICAL FEATURES The presenting symptoms are highly variable and may depend on the location, size, and duration. The common ways of presentation are shown in Box 3. DIAGNOSIS History While renal calculi may have a dull aching loin discomfort, ureteric colic waxes, and wanes with typical radiation. A past history of stone disease, family history of nephrolithiasis, and dietary history of low fluid intake, fluid loss, high intake of animal protein, salt, oxalate containing food, low calcium intake, excess intake of fructose, and vitamins C and D may aid in diagnosis. Laboratory Investigations ¢ Urinalysis: Hematuria is present in the majority. Depending on the type of stone, other urinary deposits may be seen. Calcium oxalate monohydrate crystals are dumb bell shaped, calcium oxalate dihydrate envelope shaped, cystine stones hexagonal, uric acid rhomboid shaped, and bile stained while coffin lid appearance of deposits are characteristic of struvite (Fig. 1). ¢ Estimation of urine pH may be helpful with alkaline urine favoring struvite and calcium phosphate stones and acid pH associated with uric acid stones ¢ Urine culture is often needed as associated urinary tract infections are common due to obstruction or stasis. ¢ Twenty four hour urine collection while on a normal diet and fluid intake may provide a clue to an underlying metabolic abnormality favoring nephrolithiasis. 24 hour urinary calcium excretion is ¢ Stone analysis: A knowledge of the kind of stone is useful in planning steps to prevent recurrence. Methods include wet chemical analysis, X-ray diffraction, infrared spectroscopy, and dual energy CT. DIFFERENTIAL DIAGNOSIS Several other diseases can mimic the presentation of nephrolithiasis (Box 4). TREATMENT Conservative and General Measures Asymptomatic stones may be managed on conservative lines like increasing fluid intake to at least 2 L/day. Thiazide diuretics can be tried in those with hypercalciuria. Citrate supplementation may be beneficial in those with hypocitraturia but can increase urine pH and may not be beneficial for calcium phosphate stones. Citrate hence may be avoided, if urine pH is >6.5. Allopurinol or febuxostat may be useful in hyperuricosuria. A low oxalate diet (restrict intake of spinach, potatoes, almonds etc.,) can be tried in oxalate stones while a low purine diet with minimal animal protein intake can be advised for uric acid stones. te) Differential diagnosis of nephrolithiasis. - Acute intestinal obstruction/appendicitis/diverticulitis + Acute mesenteric ischemia + Renal cell carcinoma with clot colic + Pyelonephritis/papillary necrosis + Ectopic pregnancy + Rupture/torsion of ovarian cyst + Dysmenorrhea Management of an Acute Stone Episode Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac sodium, opioids, and antispasmodic drugs can provide pain relief. Antiemetics may be needed in ureteric colic. Smaller and distal stones are likely to pass without intervention. While stones <5 mm are usually passed, it is possible to aid passage of up to 10 mm size. Good hydration and alpha blockers like tamsulosin 0.4 mg/day up to 4 weeks and calcium channel blockers (e.g., nifedipine) may aid in expulsion. Low dose steroids have also been tried. Interventional/Surgical Management Stones >10 mm are unlikely to pass spontaneously and may need surgical intervention. A septic patient with obstructive stone may need urgent decompression with either stenting or percutaneous drainage. Patients presenting with acute kidney injury also need urgent intervention. In cases of failure of stone to pass, persistent obstruction, and increasing or unrelenting colic, options are lithotripsy, endoscopic (ureteroscopic) removal or rarely open removal. External shock wave lithotripsy (ESWL) is preferred for stones <1 cm and in the proximal ureter. Ureteroscopy and endoscopy (ureteroscopic lithotripsy with electrohydraulic or laser probes) are preferred for stones >1 cm with complex renal anatomy, obesity, and those with coagulopathy as the risk of bleeding in the spleen or liver is more with ESWL. NSAIDs should be stopped 3 days prior to ESWL to minimize risk of bleeding. Percutaneous nephrolithotripsy (PCNL) and laparoscopic stone removal are other options. PREVENTION Considering the high risk of recurrence, preventive steps have to be stressed. These may differ depending on the type of stone. While liberal fluid intake can be universally advised, thiazide diuretics with a low sodium diet are advised for those with hypercalciuria, alkalinization of urine with potassium citrate for uric acid stones and drugs like Transitional cell carcinoma Ureter: Calculi Sloughed papilla Transitional cell carcinoma Compression from extrinsic tumors (uterine/cervical/ovarian) Retroperitoneal fibrosis Blood clot Stent occlusion Megaureter Bladder: Transitional cell carcinoma Blood clot Neurogenic bladder/detrusor sphincter dyssynergia Posterior urethral valve Diabetic cystopathy Urethra: Prostatomegaly Calculi Stricture se) (3) Clinical presentation of urinary obstruction. Pain/colic Decreased urinary output Hematuria (painful or painless) Renal failure Obstructive voiding/poor urinary stream Polyuria/nocturia (in some cases of chronic obstruction) Hypertension Enlarged/palpable bladder INVESTIGATIONS Urinalysis: May show microhematuria, pyuria, or crystals, though may be normal in some cases. Blood urea and serum creatinine may be elevated especially with bilateral obstruction or obstruction to a single kidney. Hyperkalemic renal tubular acidosis may be seen with chronic obstruction. Ultrasonography: This is usually the most favored investigation due to safety and cost. Dilatation of calyceal system, ureter, residual urine in the bladder, and calculi is easily detected. Renal parenchymal thinning could be an important clue to the long duration of obstruction as well as poor reversibility of renal functions. Computed tomography scan: This can be done without contrast in suspected calculus obstruction as well as in polycystic kidneys when calculus producing obstruction is suspected (Fig. 2). As it is more sensitive than ultrasound in detecting calculi, some centers prefer this to ultrasound. If renal functions are normal, contrast CT with urogram may provide additional details, if needed. Intravenous urogram can provide information on the anatomical site of obstruction, degree as well as kidney, if contrast CT scan is not feasible. Radionuclide scan provide information on individual kidney function as well as most of the information that an IVU or contrast CT urogram provides with lesser radiation exposure. Antegrade urography can delineate the site of obstruction but is rarely needed nowadays with the availability of contrast CT scan. Micturating cystourethrogram (MCU) can reveal posterior urethral valves, urethral strictures, vesicoureteric reflux, neurogenic bladder, etc. Urodynamic studies and cystoscopy can provide additional information regarding cause as well as aid in therapeutic decisions. management for neurogenic bladder and detrusor sphincter dyssynergia can be attempted after urodynamic studies to note the bladder capacity and pressure. Cholinergic drugs like bethanechol may help in decreased bladder contractility especially in diabetic cystopathy. Clean intermittent urethral catheterization every 4 hours may be needed if medical management fails as evidenced by recurrent urinary tract infections or worsening renal functions. Posterior urethral valves are a common cause for urinary obstruction in male infants and often need endoscopic fulguration of the valves. Congenital megaureters are another cause of ureteric obstruction in childhood and may need ureteric reimplantation. Ureterolysis is a form of surgical treatment tried for retroperitoneal fibrosis in case medical management with steroids and temporary ureteric stenting fail. In case of uncorrectable bladder lesions and inoperable malignancies of the genitourinary tract, urinary diversion procedures such as ureterostomy, nephrostomy, ureterosigmoidostomy, etc., may be lifesaving. As obstruction can affect the ability of the tubules to concentrate and dilute urine, relief of obstruction, especially chronic, may lead to postobstructive diuresis which may last up to a week and may need measures to prevent volume depletion and electrolyte disturbances. RECOMMENDED READINGS 1. Worcester EM, Coe EL. Calcium kidney stones. N Engl J Med. 2010;363(10):954-63. 2. Ansari MS, Gupta NP, Hemal AK, Dogra PN, Seth A, Aron M, et al. Spectrum of stone composition: structural analysis of 1050 upper urinary tract calculi from Northern India. Int J Urol. 2005;12(1):12-6. 3. Joshi A, Gupta SK, Srivastava A. Metabolic evaluation in first-time renal stone formers in North India: a single centre study. Saudi J Kidney Dis Transpl. 2013:24(4):838-43. 2e Integrating Kidney Health in Primary Healthcare Rohina Joshi WHAT IS PRIMARY HEALTHCARE? The fundamental principle of primary healthcare is that all people, everywhere, deserve the right care, in their community, throughout their life. This includes health promotion, prevention, treatment, rehabilitation, and palliation. Primary healthcare includes both individual and family healthcare along with the broader needs to the population and public health. The Declaration of Alma-Ata (1978) outlined these principles which were ratified 40 years later at the Declaration of Astana (2018). Primary care is a subgroup within primary healthcare which is defined as essential care or the first contact care provided in a community setting. A decade ago, primary healthcare in India focused on infectious diseases and maternal and child health, but with the rise in noncommunicable diseases (NCDs) due to an aging population and epidemiological transition, primary care has had to extend beyond the traditional diseases found in developing countries. The transition to NCDs prevention and management is still lagging with lack of availability of clinical guidelines, training of healthcare providers including physicians and non-physicians, availability of appropriate laboratory investigations, and medicines at the primary care level. Diseases are managed in silos within primary care, where prevention and health promotion for NCDs is not routinely practiced and patients with chronic conditions are referred to specialists for further management. HOW CAN KIDNEY HEALTH BE MANAGED IN PRIMARY CARE? In order to integrate kidney health into the primary healthcare, it is important to: e Develop evidence-based guidelines relevant to the Indian context which include guidelines for screening and management ¢ Train physicians and non-physicians in the required skills e Establish medical records which enable healthcare providers to provide continuity of care ¢ Equip primary care with functioning laboratory services e Ensure reliable supply of medications in the pharmacy e Establish clear referral pathways for further management e Increase awareness at the community level Having standardized electronic medical records and decision support tools with evidence-based guidelines for physicians and non- physicians would facilitate patient care and decrease the physician's administrative workload. At the population level, trained community health workers and nurses can screen individuals at risk of kidney disease using decision support tools and can refer them to the primary care doctor for further management. Please refer to Table 1 for further details. TABLE 1: Factors to help integrate kidney health in primary healthcare. Essential requirements Facilitators Develop and make available guidelines for _—_India specific guidelines which kidney disease screening and incorporate the traditional (diabetes management and high blood pressure) and nontraditional risk factors (infection and environmental toxins) Train physicians in the use of the Clinical decision support tools either guidelines paper based or electronic Train non-physicians to educate patientsin — Curriculum to train/retrain non- lifestyle related risk factors physicians. Communication tools (paper based or electronic) to educate patients, screen, and refer patients to physicians Up-to-date medical record system Paper based or electronic medical records Functioning equipment and laboratories Trained laboratory technicians to measure serum creatinine and urinary albumin:creatinine ratio in addition to the available laboratory tests such as fasting blood sugar Reliable supply of medications Trained pharmacists Referral pathways for further management Clear communication pathways between primary, secondary, and tertiary care Regular follow-up Train non-physicians to follow-up individuals in the community during routine home visits The goal of integrating kidney health in primary health care is to promote better health outcomes and reduce premature mortality attributable to kidney disease by educating the community, identifying people at risk of kidney disease, and managing them effectively. RECOMMENDED READINGS 1. World Health Organization. A vision for primary health care in the 21st century. Towards universal health coverage and sustainable development goals. [online] Available from https://apps.who.int/iris/bitstream/handle/10665/328065/WHO-HIS- SDS-2018.15-eng.pdf?sequence=1 &isAllowed=y (Last accessed January, 2022). 2. Dare AJ, Fu SH, Patra J, Rodriguez PS, Thakur JS, Jha P et al. Renal failure deaths and their risk factors in India 2001-2013: nationally representative estimates from the Million Death Study. Lancet Global Health. 2017;5(1). 3. Agarwal SK, Srivastava RK. Chronic Kidney Disease in India: Challenges and Solutions. Nephron Clin Pract. 2009;111:c197-203. 4, Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF, et al. What do we know about chronic kidney disease in India: first report of the Indian 3e Drug Nephrotoxicity and Dose Adjustment in Patients with Kidney Diseases Shrirang Bichu, Parag Tilve INTRODUCTION Physicians in India are caring for an increasing number of patients with renal impairment. These patients exhibit altered drug pharmacokinetics and pharmacodynamics exposing them to a greater risk of adverse effects. Hence, knowledge of drug dose modification in renal impairment is essential. Unlike in the developed world, we lack the services of ward-pharmacists who check prescriptions for inadvertent errors. This makes it imperative for physician-nephrologists to be aware of this possibility and exert extreme care. Many clinical drug trials exclude patients with renal impairment, putting this population at a disadvantage when newer drugs are needed. Fortunately, only a small proportion of drugs used in day to day clinical practice needs dose adjustments. PHARMACOKINETICS AND PHARMACODYNAMICS IN RENAL IMPAIRMENT Absorption Renal impairment can adversely affect absorption of drugs. For example, gastrointestinal tract edema can affect furosemide absorption, alkalizing effect of salivary urea on gastric secretions can affect itraconazole absorption and autonomic neuropathy can affect absorption of various drugs due to reduced contact time with gastrointestinal mucosa. Volume of Distribution Edema and ascites can increase volume of distribution for water soluble drugs (e.g., atenolol) resulting in low drug concentrations for usual doses. Plasma Protein Binding Changes in plasma protein binding can be due to low serum albumin concentration in nephrotic syndrome or due to displacement of the drugs from their binding sites by uremic toxins. For example, the protein binding of phenytoin is reduced with a resultant increase in its free fraction which predisposes to toxicity at usually acceptable total plasma concentrations. Metabolism Drug metabolism is largely a function of the liver. Kidney is a site of metabolism of some drugs (e.g., insulin metabolism and conversion of 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3) and in renal impairment drug metabolism can be slowed or altered (e.g., imipenem). Elimination Kidney is the major organ for drug elimination. Renal drug excretion depends on glomerular filtration rate (GFR), renal tubular secretion, and tubular reabsorption. The clearance of drugs and metabolites excreted by the kidney falls with the drop in GFR and their half-life gets prolonged. This is the chief mechanism of altered drug pharmacokinetics in patients with renal impairment. Pharmacodynamics 
