Treatment and Prevention of Common Complications of Chronic Kidney Disease

Chronic kidney disease (CKD) is a worldwide public health problem with an increasing incidence and prevalence. Outcomes of CKD include not only complications of decreased kidney function and cardiovascular disease but also kidney failure causing increased morbidity and mortality. Unfortunately, CKD is often undetected and undertreated because of its insidious onset, variable progression, and length of time to overt kidney failure. Diabetes is now the leading cause of CKD requiring renal replacement therapy in many parts of the world, and its prevalence is increasing disproportionately in the developing countries. This review article outlines the current recommendations from various clinical guidelines and research studies for treatment, prevention and delaying the progression of both CKD and its common complications such as hypertension, anemia, renal osteodystrophy, electrolyte and acid-base imbalance, and hyperlipidemia. Recommendations for nutrition in CKD and measures adopted for early diabetic kidney disease to prevent further progression have also been reviewed. There is strong evidence that early detection and management of CKD can prevent or reduce disease progression, decrease complications and improve outcomes. Evidence supports that achieving optimal glucose control, blood pressure, reduction in albuminuria with a multifactorial intervention slows the progression of CKD. Angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists are most effective because of their unique ability to decrease proteinuria, a factor important for the progression of CKD.


Treatment and Prevention of Common Complications of Chronic Kidney Disease
obstruction, tubulo-interstitial nephropathy and infiltrative diseases.Studies in South Asian countries including Bangladesh have shown glomerulonephritis to be the most common cause of end stage renal disease (ESRD) followed by DM. [3][4][5] The most frequent cause of CKD in North America and Europe is DM followed by hypertension. 6Diabetes mellitus is now becoming increasingly prevalent in developing countries, perhaps due to change in dietary habits, diminished physical activity and weight gain. 6herefore, DM is now the leading cause of ESRD requiring renal replacement therapy (RRT) in many parts of the world, and its prevalence is increasing disproportionately in the developing world. 6Patients with newly diagnosed CKD often also present with hypertension.When no overt evidence for a primary glomerular or tubulointerstitial kidney disease process is present, CKD is often attributed to hypertension. 6The incidence of ESRD in our country is not known, but would be much higher than that in developed countries because of high incidence of infection and environmental pollution as well as increasing prevalence of DM.
This article critically reviews the current recommendations and therapeutic strategies published in recent journals and various clinical guidelines for treatment and preventing or delaying the progression of CKD and it's common complications.

Definition of chronic kidney disease
The National Kidney Foundation (NKF), an organization in United States defines CKD as either kidney damage or decreased kidney function for 3 months or more. 7The definition of CKD is the same regardless of age, sex and race.[10][11][12][13] Decreased kidney function means a glomerular filtration rate (GFR) of less than 60 mL p e r minute per 1.73 m 2 body surface area. 7A GFR rate of more than 60 mL/min/1.73m 2 i s considered abnormal if it is accompanied by documented evidence of kidney damage.The principal marker of kidney damage is the presence of persistent protein in urine.Other evidence of kidney damage includes abnormalities in urine sediment, blood and urine biochemistry, or abnormal findings in imaging studies. 79]14 H o wever, microalbuminuria or 24-hour urinary albumin excretion in the range of 30 to 300 mg indicates the early stage of kidney disease in DM. 15

Glomerular filtration rate (GFR)
The GFR is the best measure of overall kidney function. 7The normal level of GFR varies according to age, sex, and body size.In healthy young adult of 30 years or younger, the normal GFR is approximately 125 mL/min per 1.73 m 2 and declines by approximately 1 mL/min per 1.73 m 2 per year thereafter. 7Estimation of the GFR no longer requires a 24-hour urine collection for creatinine clearance; it can be accomplished with similar accuracy using mathematic formulas.Most commonly used formulas are the Modification of Diet in Renal Disease (MDRD) equation and the Cockcroft-Gault equation (Table I).Many laboratories now report an estimated GFR (eGFR), using one of these equations.The MDRD has the advantage of being more accurate than the Cockcroft-Gault in persons with a GFR less than 90 mL/min per 1.73 m 2 and takes race into consideration. 7,16,17][20] However, in people aged over 70 years, an eGFR in the range 45-59 mL/min/1.73m 2 , if stable over time and without any other evidence of kidney damage, is unlikely to be associated with CKD related complications.

Stages of CKD
The NKF classifies CKD into five stages (Table II) based on the GFR and/or presence of kidney damage. 710][11][12][13] Table II: Classification of chronic kidney disease 7 Stage GFR (mL/min per 1.73 m

Advanced chronic kidney disease, kidney failure and end stage renal disease
Stages 4 and 5 are sometimes called advanced CKD. 2 The NKF guidelines define kidney failure as either 1) GFR less than 15 mL/min per 1.73 m 2 , which is accompanied in most cases by signs and symptoms of uremia, or 2) a need to start RRT. 7The dispiriting term ESRD represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome.This syndrome leads to death unless the toxins are removed by RRT, using dialysis or kidney transplantation.

Management
Maintenance of euvolemia (fluid balance) It has been suggested to limit sodium intake for its effects on both fluid balance and blood pressure. 24,25n advanced CKD, the kidney is unable to adapt to large changes in sodium intake.Intake >3-4 g/day can lead to hypertension and volume overload, whereas intake of <1 g/day can lead to volume depletion and hypotension.A goal of 2 g/day of sodium is reasonable for most patients.A daily intake of 2 L of fluid maintains water balance. 25But overzealous salt restriction or diuretic use can lead to extracellular fluid volume depletion and precipitate a further decline in GFR.Patients with salt-losing nephropathy may require a sodium-rich diet or salt supplementation. 6,24

Hyperkalemia
Hyperkalemia often responds to dietary restriction of potassium, avoidance of potassium supplements as well as potassium-retaining medications [especially spironolactone, angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs)], or the use of kaliuretic diuretics such as metolazone.Metolazone promotes urinary potassium excretion, while a potassium-binding resin, such as calcium resonium or sodium polystyrene, promotes potassium loss through the gastro-intestinal tract and may reduce the incidence of hyperkalemia in CKD patients. 25 Acute hyperkalemia: calcium chloride or gluconate intravenously, insulin administration with glucose intravenously, bicarbonate intravenously, and potassium-binding resin orally or per rectum, cardiac monitoring.25 Intractable hyperkalemia is an indication (although uncommon) to consider institution of dialysis in a CKD patient.25 b) Chronic hyperkalemia: dietary potassium restriction and sodium polystyrene, 15-30 g once daily orally in juice or sorbitol.25

Acidemia
It has been suggested that in presence of acidemia oral alkali therapy can slow CKD progression. 25The plasma bicarbonate should be maintained >22 mmol/L by giving sodium bicarbonate supplements (starting dose of 1 g 8-hourly, increasing as required). 6,24I t m u st be remembered that the increased sodium intake may induce hypertension or edema. 24

Hypertension
Hypertension is commonly associated with CKD in more than 75% of patients. 26Various target blood pressures have been suggested, for example, 130/80 mm Hg or less for CKD alone, and lowered to 125/75 mm Hg for those with proteinuria >1 g/day. 6,7,24,27,28 InD if hypertension is associated with significant proteinuria (0.5 g/24 h or more), ACE inhibitors/ ARBs should be offered because of their unique ability to decrease proteinuria preferentially by lowering intra-glomerular pressure. 2,27In hypertension with urinary protein excretion <0.5 g/24 h, ACE inhibitors, ARBs, long-acting calcium channel blockers, thiazide diuretics or beta-blockers can be used. 2en ACE inhibitor/ARB therapy is started, some patients with CKD may have an initial decrease in GFR, a mild increase in the serum creatinine concentration, and a mild increase in the potassium level. 29Therefore, in people with CKD, serum creatinine and potassium levels should be measured and the GFR should be estimated before starting ACE inhibitor/ARB therapy.These measurements should be repeated between 7 th and 14 th day after starting ACE inhibitor/ARB therapy and after each dose increase. 2ACE inhibitor/ARB therapy should not normally be started if the pretreatment serum potassium concentration is significantly above the normal reference range.ESAs are less effective in the presence of iron deficiency, active inflammation, malignancy, intercurrent illness, or in patients with aluminium overload, which may occur in dialysis. 24The use of ESAs for the treatment of anemia in patients with CKD is associated with potential adverse outcomes, including increased blood pressure, thrombotic complications (like stroke) and possibly other CVD events. 25,27 Iron therapy is an important component of anemia management.Iron supplementation is usually essential to ensure an optimal response to ESAs in patients with CKD because the demand for iron by the marrow frequently exceeds the amount of iron that is immediately available for erythropoiesis (measured by percent transferrin saturation), as well as the amount in iron stores (measured by serum ferritin).In CKD, a serum ferritin <100 ng/mL or iron saturation <20% is suggestive of iron deficiency. 25Iron stores should be repleted prior to the initiation of ESAs.For the CKD patient not yet on dialysis, oral iron supplementation should be attempted.If there is GI intolerance, the patient may have to undergo intravenous (IV) iron infusion. 6eople receiving ESA maintenance therapy should be given iron supplements to keep their serum ferritin levels between 200 and 500 ng/mL. 2 Iron therapy should probably be withheld if the serum ferritin is >500 ng/mL, even if the iron saturation is <20%. 25Oral therapy with ferrous sulfate, gluconate, or fumarate, 325 mg once to three times daily, is the initial therapy in CKD. 25 F o r patients on hemodialysis, IV iron can be administered during dialysis.In addition to iron, an adequate supply of other major substrates and cofactors for red cell production must be ensured, including vitamin B 12 and folate. 25 Red cell transfusion to treat anemia in CKD becomes necessary sometimes.In people with anemia of CKD in whom kidney transplant is a treatment option, red cell transfusions should be avoided if possible, to minimize the risk of alloimmunization related to their use.

Chronic kidney disease-mineral bone disorders (CKD-MBD)
In CRF, hypocalcemia results from inadequate production of 1 , 2 5 -dihydroxycholecalciferol (calcitriol) by the kidneys needed for calcium retention and resorption.Hyperphosphatemia is a consequence of reduced urinary phosphate excretion due to declining GFR.Phosphorus complexes with calcium, deposits in soft tissues and causes soft tissue calcification.Hypocalcemia, decreased calcitriol and hyperphosphatemia stimulates the parathyroid glands for secretion of excessive parathyroid hormone (PTH) resulting in secondary hyperparathyroidism.This typical pattern of hyperphosphatemia, hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism is seen as early as CKD stage 3. 25 Excessive PTH helps to maintain calcium levels mainly by bone resorption and causes osteitis fibrosa and other disturbances like osteomalacia, osteoporosis and osteosclerosis. 24hese disturbances have traditionally been termed renal osteodystrophy. 31D i sturbances in mineral metabolism also results in vascular calcification due to deposition o f c a lcium phosphate complex, resulting in vascular rigidity and occlusion which may be partly responsible for the accelerated CVD and excess mortality seen in the CKD population.As the disorder is not confined to the skeleton, in 2005, the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice proposed replacing the term renal osteodystrophy by CKD-MBD. 32CKD-MBD is manifested by an abnormality of any one or a combination of the following disorders-laboratory-abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone-changes in bone turnover, mineralization, volume, or strength and calcification in the soft-tissue and the arterial vessels. 31,32 Control of hyperphosphatemia is the first step in the treatment of CKD-MBD.25 This involves dietary phosphorus restriction initially, followed by the administration of oral phosphorus binders if targets are not achieved.Examples of foods with high phosphate content are milk, cheese, eggs, nuts, peas, beans, colas, and dairy products.24 Oral phosphorus binders, such as calcium carbonate/gluconate (500 mg/tablet, maximum 3 gm daily) or calcium acetate (667 mg/capsule, maximum 1500 mg daily) block absorption of dietary phosphorus in the gut and are given thrice daily with meals. Thse should be titrated to a serum phosphorus of <4.5 mg/dL in stage 3-4 CKD and <5.5 mg/dL in ESRD.A major side-effect of calcium-based phosphate binders is hypercalcemia.Therefore doses should be decreased or stopped if serum calcium rises above 10 mg/dL.25 Phosphorus-binding agents that do not contain calcium are aluminium hydroxide, sevelamer and lanthanum.Sevelamer, 800-3200 mg and lanthanum carbonate, 500-1000 mg are given at the beginning of meals and may be combined with calciumcontaining binders.6,25 Aluminium exposure should be avoided.High levels of aluminium may be present in impure dialysate water. 25Aluminium hydroxide is a highly effective phosphorus binder, but can cause osteomalacia and neurologic complications when used long-term.It can be used in the acute setting for serum phosphorus >7 mg/dL or for short periods (e.g., 3 weeks) in CKD patients; however, long-term use should be avoided.25 b) Secondary hyperparathyroidism can be prevented by restricting dietary phosphate intake, u s ing a calcium-based phosphate binder, and administering calcitriol.33 Best practice is to maintain normal calcium, phosphate, and 1, 25-dihydroxycholecalciferol.Once serum phosphorus levels are controlled, active vitamin D (calcitriol) or active vitamin D analogues are recommended to treat secondary hyperparathyroidism (if PTH more than twice normal) or hypocalcaemia in stage 3-5 CKD.24,25 Typical calcitriol dosing is 0.25 or 0.5 mcg orally daily or every other day.25 Serum 25-OH vitamin D levels should be measured and brought to normal by vitamin D supplementation.34 When vitamin D supplementation is indicated in people with CKD, certain clinical guidelines recommend cholecalciferol or ergocalciferol to people with stage 1, 2, or 3 CKD and calcitriol or 1-alpha-hydroxycholecalciferol (alfacalcidol) to people with stage 4 or 5 CKD.35 The routine measurement of serum calcium, phosphate, and PTH levels in people with stage 1, 2, 3 CKD is not recommended, but needs measurement in people with stage 4 or 5 CKD.35 Calcitriol therapy may result in hypercalcemia and/or hyperphosphatemia through increased GI absorption of these minerals.The dose of calcitriol should be decreased or stopped if hypercalcemia or hyperphosphatemia occurs. 2 C a lcitriol exerts a direct suppressive effect on PTH secretion and also indirectly suppresses PTH secretion by raising the concentration of ionized calcium.Certain analogues of calcitriol (e.g., paricalcitol) are available that suppress PTH secretion with less attendant hypercalcemia.6 C a lcimimetic agents (e.g., cinacalcet) which enhance the sensitivity of the parathyroid cell to the suppressive effect of calcium have been developed recently.This class of drug produces a dose-dependent reduction in PTH production and plasma calcium concentration.6,35 Cinacalcet, 30-90 mg orally once a day, can be used if elevated serum phosphorus or calcium levels prohibit the use of vitamin D analogues.25 In 2009 KDIGO clinical practice released guidelines on the management of CKD-MBD which suggests that, if the PTH levels fall below two times the upper limit of normal for the assay, calcitriol or calcimimetics be reduced or stopped.6,35 c) Tertiary hyperparathyroidism: Even with appropriate medical therapy, some patients continue to have refractory hyperparathyroidism because of parathyroid gland hyperplasia.In patients with severe hyperparathyroidism who fail to respond to medical/pharmacological therapy, the KDIGO guideline suggests parathyroidectomy.35

Dyslipidemia
Dyslipidemia is a common complication of progressive CKD and a primary risk factor for CVD.The goals are an LDL cholesterol level below 100 mg per dL (2.60 mmol per L) and a triglyceride level below 200 mg per dL (2.26 mmol per L). 36Statins should be offered to people with CKD for the secondary prevention of CVD irrespective of baseline lipid values. 2 F i brates are known to decrease triglyceride levels, but they may increase the risk for rhabdomyolysis in patients with CKD. 27

Antiplatelet drugs
Antiplatelet drugs should be offered to people with CKD for the secondary prevention of CVD. 2

Hyperuricemia
There is also theoretic value in lowering uric acid levels in CKD patients with concomitant hyperuricemia, but clinical data regarding benefit are still lacking. 25

Nutrition
Counseling on adequate and appropriate nutrition should be provided at each office visit.Dietary advice should be offered to people with progressive CKD concerning protein, calorie, salt, potassium and phosphate intake, when indicated. 2 a) Protein intake: The effect of dietary protein restriction on kidney disease is the subject of debate.
There is a lack of convincing evidence that the longterm restriction of protein intake (<0.70 g/kg/day) delays the progression of CKD. 6,27Nonetheless, restriction of dietary protein intake has been recommended for CKD patients.For non-diabetic and diabetic patients with CKD stage 4, two systematic reviews and one meta-analysis suggested that, in comparison to other treatments, there was, at most, a modest benefit associated with restricting protein leading to a delay in CKD progression. 37,38igh protein intakes are associated with high phosphate intakes as foods that contain protein also tend to contain phosphate.It would appear prudent to avoid high protein intakes in stage 4 CKD patients when hyperphosphatemia is prevalent.The ADA recommends reduction of protein intake to 0.8-1.0g/kg body wt/day in individuals with diabetes and the earlier stages of CKD and to 0.8 g/kg body wt/day in the later stages of CKD that may improve renal function. 391][42] It is further advised that at least 50% of the protein intake be of high biologic value. 6enefits of protein restriction in slowing decline of GFR must be weighed against the risk of malnutrition and cachexia upon the initiation of dialysis. 25 Energy intake: An adequate nutrition with daily caloric intake of 30 to 35 kcal per kg/day in patients with CKD has been recommended.6,7 c) Salt and water restriction: A goal of 2 g/day of sodium intake is reasonable for nondialysis patient approaching ESRD; a daily intake of 2 L of fluid maintains water balance.25 Patients with salt-losing nephropathy may require a sodium-rich diet or salt supplementation.6 d) Potassium restriction: A goal of <50-60 mEq/day intake of potassium is adequate.Restriction is needed once the GFR has fallen below 10-20 mL/min/1.73m 2 , or earlier if the patient is hyperkalemic. 25 Phosphorus restriction: Phosphorus needs to be restricted to 800-1000 mg/day.Foods rich in phosphorus such as cola beverages, eggs, dairy products, nuts, beans, and meat should be limited, although care must be taken to avoid protein malnutrition.25 P h osphorus-containing medicines, particularly cathartics should be avoided.25 f) Magnesium-containing medications, such as laxatives and antacids are contraindicated.Many drugs are excreted by the kidney; dosages should be adjusted for GFR. 25

Lifestyle advice
Most patients with CKD will die of events related to CVD before ESRD develops. 43Therefore, an important focus of care for patients with CKD includes management of cardiovascular risk factors.
People with CKD should be encouraged at each office visit to take regular exercise, achieve a healthy weight and stop smoking completely.Smoking is a strong risk factor for cardiovascular mortality in patients with CKD. 44It is also strongly associated with the progression of nephropathy. 44A t a rget weight of BMI <23 should be ideal. 2

Treatment of underlying cause for preventing progression of CKD
Treatment of the underlying cause of CKD is vital.These include optimized glucose control in diabetes mellitus, immunomodulatory agents for glomerulonephritis, and emerging specific therapies to retard cytogenesis in polycystic kidney disease. 6,25

Diabetes
Control of diabetes should be aggressive in early CKD; excellent glycemic control reduces the risk of kidney disease and its progression. 25The American Diabetes Association (ADA) and Canadian guidelines recommend that plasma values for preprandial glucose be kept in the 5.0-7.2mmol/L (90-130 mg/dL) range and hemoglobin A 1C should be <7% to prevent progression of CKD in patients with DM. 27,45 The half-life of insulin is prolonged in CKD due to reduced tubular metabolism of insulin; patients on insulin therapy may need progressive reduction in dose as their renal function worsens.Risk of hypoglycemia increases in advanced CKD, and glycemic targets may need to be relaxed to avoid this dangerous complication. 24M a ny hypoglycemic agents such as metformin require dose reduction in renal failure, and some are contraindicated when the GFR is <50 mL/min/1.73m 2 . 25Metformin can cause lactic acidosis; and the thiazolidinediones (e.g., pioglitazone) may increase renal salt and water absorption and aggravate volume-overload states, and contribute to adverse cardiovascular events. 6E inhibitors or ARBs should be used in individuals with microalbuminuria as well as with macroalbuminuria irrespective of presence of hypertension in diabetes. 9ACE inhibitors and ARBs are effective at reducing proteinuria, slowing the decline in GFR and retarding the progression of diabetic kidney disease. 2 The definition of hypertension in DM or diabetic kidney disease (DKD) is blood pressure of 130/80 mm Hg or greater. 46In patients with diabetes having kidney disease and hypertension, treatment with ACE inhibitors or ARBs has been recommended by various guidelines to prevent progression of CKD.

Key clinical recommendations
Early detection and management of CKD can prevent kidney disease progression and decrease its complications.All patients should be assessed to determine their susceptibility to or development of CKD.The clinical evaluation should include analysis for risk factors, markers of CKD (e.g.assessment for persistent a l buminuria), GFR estimation, and a treatment plan to slow the progression.In CKD patients, where kidney transplant is a treatment option, red cell transfusions should be avoided if possible. 2g) Epidemiologic studies in humans show an association between elevated phosphorus levels and increased risk of cardiovascular mortality in early CKD through ESRD. 25 C o ntrol of hyperphosphatemia is the first step in the treatment of CKD-MBD. 25While using calcium-based phosphorus binders, hypercalcemia must be avoided to prevent aggravation of soft tissue and vascular calcification leading to increased cardiovascular morbidity and mortality.
h) Protein restriction may be effective in slowing the progression of CKD, especially proteinuric and diabetic renal diseases.Benefits of protein restriction in slowing decline of GFR must be weighed against the risk of malnutrition and cachexia upon the initiation of dialysis. 25

Conclusion
The incidence of CKD is increasing worldwide and unfortunately, CKD is often undetected and undertreated because of its insidious onset, variable progression, and length of time to overt kidney failure.Its natural course is an eventual decline in the GFR, leading to kidney failure and the need for RRT.
The goal of therapy is to detect CKD early to delay its progression, thereby reducing associated complications and adverse outcomes of kidney disease.Patients with one or more risk factors should have their GFR estimated and be assessed for persistent albuminuria.6][57][58][59] ACE inhibitors are more effective than other antihypertensive drugs i n preventing the progression of kidney disease in diabetic and nondiabetic patients.Other interventions studied to reduce progression include correction of anemia, treatment of CKD-MBD, dietary protein restriction, and lipid-lowering therapy.

Table I :
Recommended equations for estimation of GFR 2,6 30 t h a s been suggested by investigators in one study that the decision to transfuse a CKD patient with non-acute anemia should not be based on any arbitrary Hb threshold only, but should be determined also by the occurrence of symptoms caused by anemia.In particular, they suggest considering transfusion at Hb values <7 g/dL o r a t H b v a lues <8 g/dL i n postoperative surgical patients.30 2,[8][9][10][11][12][13] 36aluation, and Treatment of High Blood Pressure recommends a target blood pressure of less than 130/80 mm Hg in patients with chronic kidney disease.28d)Topreventprogression of nephropathy in patients with DM, the ADA recommends glycemic control, with the goal being a HbA1C <7 percent.45e)Themostrecent guidelines from the NKF recommend treating dyslipidemia aggressively in patients with CKD.The goals are a LDL cholesterol level below 100 mg per dL (2.60 mmol/L) and a triglyceride level below 200 mg per dL ( 2 .26mmol/L).36f) Anemia in CKD responds to ESAs.Iron therapy is an important component of anemia management in CKD.The target goal of Hb is 10-11 g/dL.