According to KDOQI-CKD guideline, all individuals with a glomerular filtration rate (GFR) <60
mL/min/1.73 m2 for longer than 3 months are classified as having CKD, irrespective of the
presence or absence of kidney damage.
All individuals with kidney damage are classified as having CKD, irrespective of the GFR level.
Kidney damage is defined as microscopic hematuria, proteinuria, or anatomic abnormalities of the
kidneys. Patients who are classified as having stage 5 CKD, who are on dialysis are considered to
have an endstage renal disease (ESRD).
Among the diseases leading to ESRD, DM, HTN, and glomerulonephritis are still the most common
etiologies.
Obesity increases the risk for CKD in the general population, and the association appears to be
stronger in women than in men.
Effective strategies can slow the progression of CKD and reduce the risk of cardiovascular mortality
and ESRD. The primary strategies are blood pressure control, preferably with agents that block the
renin-angiotensin-aldosterone pathway and good glycemic control.
Lipid-lowering therapies, irrespective of the starting cholesterol concentration, reduce the incidence
of major atherosclerotic events in patients with CKD.
The correction of acidosis is thought to slow declining in GFRs, countering acidosis in the early CKD is
important.
sodium-glucose cotransport-2 inhibitor (SGLT2 inhibitor), was shown to be effective in slowing the
progression of CKD in patients with DM; it also confers cardiovascular protection.
The 2019 American Diabetes Association (ADA) guidelines recommend SGLT2 inhibitors as the
preferred class of agents to be added after metformin in patients with type2 DM and a history of
heart failure or CKD.
Recently, there has been considerable interest in using cystatin C as an alternative or complementary
marker to creatinine for estimation of GFR and maybe particularly advantageous in patients with higher
GFR levels.
The combination of serum creatinine and cystatin C in a single equation has been shown to consistently
provide more accurate eGFR than equations using ether marker alone.
It can be used as a confirmation of the diagnosis of CKD in a patient with estimated GFR 45 -60 ml
/min/m2 and no other evidence of kidney disease, such as albuminuria or radiographic abnormalities.
Proteinuria is one of the most important parameters in the clinical evaluation of chronic kidney disease
for several reasons. Albuminuria, rather than proteinuria has become more in use clinically, and
guidelines classify kidney disease by level of albuminuria.
Guidelines recommend aiming for systolic blood pressure less than 130 mmHg and diastolic blood
pressure less than 80 mmHg in all patients with CKD regardless of the degree of proteinuria.
The use of ACEI and ARBs is now well established for the treatment of proteinuric CKD and is therefore
part of the AHA/ACC 2017 HTN guidelines.
Though K/DOQI guidelines recommend that CKD stages 4–5 patients start furosemide at a dose of 40–
80 mg once daily with weekly titration upward, it is often desirable to dose furosemide twice or thrice
daily, if pill burden or nocturia limits more frequent dosing, then a trial of a different loop diuretic
possessing superior pharmacokinetics (bumetanide) or a longer half-life (torsemide) may increase
efficacy.
It had been believed that thiazide diuretics were essentially ineffective at GFR < 30 ml/min. However,
chlorthalidone, indapamide, and metolazone have longer half-lives than hydrochlorothiazide and,
therefore, provide greater net urinary sodium excretion. Clinical trials suggest that long-acting thiazides
can successfully reduce BP even in advanced CKD and when combined with loop diuretics.
In patients with hypertensive renal disease, there is decreased urinary uric acid excretion, and
depending upon gastrointestinal excretion, it may lead to hyperuricemia.
Chronic hyperuricemia stimulates the renin-angiotensin system and inhibits release of nitric oxide,
contributing to renal vasoconstriction and increasing BP.
correction of the hyperuricemic state significantly improves BP control, decreases proteinuria, and
slows the progression of renal disease.
Allopurinol treatment slowed down renal disease progression independently of age, gender,
diabetes, C-reactive protein, albuminuria, and use of renin-angiotensin system blockers.
Infections are a leading cause of increased morbidity and mortality in patients with chronic kidney
disease (CKD). Patients with CKD experience immune dysfunction which is independent of the
etiology of their CKD, and this may increase their risk of acquiring infections.
The clinical manifestations can vary from acute kidney injury (AKI) to acute or chronic
glomerulonephritis (GN), nephrotic syndrome, and rapidly progressive GN.
Metabolic acidosis of CKD is associated with a plethora of complications. Acidemia leads to chronic
inflammation, dissolution of bone, muscle degradation, growth retardation, and dysregulation of
insulin. Metabolic acidosis of CKD accelerates the worsening of chronic kidney disease and
increases mortality.
low bicarbonate levels in serum correlated with low serum albumin levels in patients with CKD.
Sodium bicarbonate tablets usually come in aliquots of 300–650 mg per tablet. With their use, one is
able to administer at least 3.7–8 mEq of sodium bicarbonate per tablet.
Phosphate binders such as calcium acetate, calcium citrate, and sevelamer carbonate as a secondary
function can help improve acidemia as they have precursors of bicarbonate.
As chronic kidney disease progresses, the ability of the kidney to concentrate or dilute is progressively
impaired. Hence, one can speculate that sodium disorders would have a higher prevalence in the
chronic kidney disease population.
Sodium disorders are common in end-stage renal disease patients with hyponatremia, being more
common than hypernatremia.
There is a strong association of hyponatremia and mortality in end-stage renal disease patients.
Vasopressin levels are elevated in chronic kidney disease. Due to the inability of the collecting duct to
respond to vasopressin, the urine cannot concentrate. Administration of vasopressin does not restore the
ability to concentrate further implying resistance at the receptor level.
Uremic also blunts intracellular response to vasopressin by a reduction in cyclic AMP.
Anemia is a common complication that occurs during chronic kidney disease (CKD).
Having diabetes and chronic kidney disease increases the risk of anemia, the main treatment of anemia of
CKD is recombinant human erythropoetin (rHuEPO).
Epo alpha and derivatives:
50–100 units/kg × 1 week 10,000–20,000 every other week
50–100 units/kg × 3 week for dialysis patients
Oral iron remains one of the cornerstones of anemia therapy in pre-dialysis CKD.
The most common used form of oral iron continues to be ferrous sulfate as it is inexpensive and widely
available. Ferric gluconate, ferric succinate, and iron polymaltose are less commonly used.
Ascorbic acid or vitamin C has been used not only to facilitate gastrointestinal absorption of iron but
also to increase iron release form the reticuloendothelial depots.
Agents that inhibit Hypoxia Inducible Factor prolyl-hydroxylases can not only improve EPO production
but also facilitate iron mobilization from stores and increase iron absorption from the gastrointestinal
tract. In comparison to EPO, their route of administration is oral. There are currently six drugs in the
family that are undergoing trials in the USA and other countries: roxadustat, vadadustat, daprodustat,
molidustat, enarodustat, and desidustat.
Currently, HIF-1 alpha stabilizers are approved in China for anemia treatment in CKD and dialysis
populations and in Japan for the treatment of anemia in the dialysis patients
Patients with advanced CKD have a wide range of abnormalities involving mineral ions and bone.
Depending on factors such as the stage of CKD, and medications used, some patients have evidence
of pathologically increased PTH action in the bone (osteitis fibrosis cystica), while some others have
insufficient PTH action in the bone (adynamic bone disease).
At every stage of CKD, there are clinical manifestations of the disrupted mineral ion homeostasis,
namely an increased risk of fractures and adverse cardiovascular events.
Klotho is a co-receptor for FGF23. Together they play an important role in bone mineral and vitamin
D metabolism.
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate
reabsorption and vitamin D hormone synthesis in the kidney. The endocrine actions of FGF23 in the
kidney are αKlotho-dependent, because high-affinity binding of FGF23 to FGF receptors requires the
presence of the co-receptor αKlotho on target cells. It is well established that excessive
concentrations of intact FGF23 in the blood lead to phosphate wasting
Patients with CKD have more than fourfold higher risk of fracture than the non-CKD population.
Among patients with CKD-MBD, those with high PTH, calcium, and phosphorus have the highest risk of
cardiovascular hospitalization and death.
More than 80% of adults on dialysis, including young adults, have evidence of coronary artery
calcification.
Calciphylaxis is a form of vascular calcification affecting the intima and media of small- and medium-
sized arteries of the subcutaneous tissues, leading to tissue ischemia. The use of calcium supplements
or vitamin D to suppress PTH is a risk factor for calciphylaxis.
Patients living with advanced CKD have ten times higher serum levels of beta-2- microglobulin
(B2M), a protein that is part of HLA-1 complexes and 97% renally cleared. Accumulated and
modified (i.e., by advanced glycation end products) B2M predominantly deposits in the
osteoarticular surfaces and generates corresponding clinical manifestation.
Carpal tunnel syndrome is the most prevalent of these manifestations. Rotator cuff tendinitis from
B2M amyloid can present as unexplained shoulder pain in patients that have been on long-term
dialysis (i.e., >10 years).
In CKD patients with stages 3–5, the use of DXA scan for osteoporosis screening, similarly to non-
CKD population has been recently recommended by KIDGO guidelines in CKD patients. This
recommendation is based on the results of cohort studies that demonstrate that DXA-measured
bone mineral density predicts risk of fracture in CKD patients and can help to risk-stratify patients
to treatment with new osteoporosis medicines that are now available for patients with reduced
GFR.
It is recommended to maintain normal levels of phosphorus to avoid hypercalcemia. Phosphate-
lowering strategies include dietary interventions, use of phosphate binders, and renal replacement
therapy.
Types of phosphate binders include aluminum hydroxide, calcium containing (i.e., calcium acetate),
non-calcium-containing (i.e., sevelamer), and iron-based binders (i.e., ferric citrate).
Avoid calcium-containing binders, especially in patients with elevated calcium levels.
For patients with GFR >30 ml/ min, FDA-approved medications include bisphosphonates,
denosumab, and teriparatide for mineral density. Denosumab can cause severe hypocalcemia,
especially in CKD, thus this needs to be monitored.
The use of non-calcium-containing binders is also preferred for patients with calciphylaxis
Warfarin should be discontinued in all patients with calciphylaxis. If anticoagulation is needed,
apixaban may be an option for a select group of ESKD patients.
Observational studies suggest that sodium thiosulfate, systemic or intralesional, may provide benefit in
the treatment of calciphylaxis and should be considered for all patients. The adverse effects of this
include metabolic acidosis, QT prolongation, and hypocalcemia.
Chronic kidney disease and pregnancy:
During pregnancy, kidneys increase in size by about 1–1.5 cm in length secondary to an increase in
renal volume by up to 30%. A physiologic hydronephrosis occurs due to the influence of progesterone
hormone inhibiting ureteral peristalsis and to the mechanical obstruction of the ureter (right > left)
due to dextrorotation of the uterus by the sigmoid colon.
Pregnancy-associated acute kidney injury (AKI) is a rare but serious complication and has signifcant
adverse outcomes.
Progression of CKD results in diminished fertility, and women on long-term dialysis get pregnant rarely.
Moreover, human chorionic gonadotropin levels are inversely related to GFR and therefore results must
be interpreted with caution. Pregnancy in women with underlying CKD is associated with a significant
risk factor for adverse outcome.
women with stage 1 CKD and hypertension and/or proteinuria should be followed closely during
pregnancy due to an increased risk of preeclampsia, intrauterine growth retardation, preterm delivery,
prematurity, small for gestation age, fetal loss, or neonatal death compared to women with normal
renal function.
Moreover, pregnancy can accelerate the renal disease progression, such as development of
hypertension, increase in proteinuria, and decrease in GFR, either reversible or irreversible, leading to
the so-called CKD shift and the need to start dialysis earlier than anticipated.
KDOQI recommends protein 0.6–0.75 g/kg/day for patients with CKD.
Hyponatremia:
Hypovolemic Hyponatremia Secondary to Volume Deficits
If a patient developed hyponatremia, diuretics (loop diuretics) should be discontinued, and
administration of normal saline is usually the fluid of choice. Close monitoring is required as these
patients can conversely hold on to sodium and can very easily tip into hypervolemia.
Euvolemic/Hypervolemic Hyponatremia
For patients with chronic kidney disease who developed euvolemic hyponatremia, the removal of
offending agents is paramount. Antidepressants, anticonvulsants, and anti-psychotics are the most
common class of drugs responsible for SIADH. ADH inhibitors can help with free water removal by
antagonizing the effect of vasopressin.
Hypernatremia and Chronic Kidney Disease:
Hypernatremia can develop in chronic kidney disease in the setting of a lack of free water ingestion and
the kidneys’ inability to concentrate urine. Treatment includes enteral or parenteral free fluid repletion.
Hyperkalemia:
The use of diuretics is reserved for patients who require volume management as well as blood pressure
control. Hypovolemia can occur with the use of diuretics that reduces GFR and can exacerbate
hyperkalemia.
Sodium Polystyrene Sulfonate is a sodium-based exchange resin. It exchanges sodium for potassium,
calcium, and ammonia. medication is admin istered either orally or rectally. The effectiveness of the oral
route has a lag of at least 6–8 hours due to its transit to the distal colon. Doses between 60 and 80 g can
reduce potassium levels by 0.9–1.7 millimoles per L. As per the FDA, the administration should be limited
to 3 hours before and after oral medications. Studies have shown that certain medications such as amlo
dipine, metoprolol, amoxicillin, Lasix, phenytoin, and warfarin are more likely to bind.
Calcium Polystyrene Sulfonate:
it is a calcium-based exchange resin which can be administered both orally and in certain cases rectally
once diluted with sorbitol. Side effects include constipation, hypercalcemia, and hypercalciuria. Dose
between 2.5 and 15 g per day was found to decrease potassium values in 70% of patients by
0.3 mmol/L
Patiromer:
Patiromer was approved for the treatment of chronic hyperkalemia in October of 2015. It is a calcium-
based resin that exchanges divalent ion for potassium. The product is reconstituted in water and
administered orally. Starting dose is 4.2 g twice a day with escalation to a maximum of 16.8 g twice a
day. Patients in these studies were able to continue on their RAAS blockers. Reduction in potassium
was dose-related.
Sodium Zirconium Cyclosilicate:
This is a zirconium-based exchange resin which was approved by the FDA in May 2018. The selective
exchange is between potassium and sodium for ammonium and hydrogen in the gastrointestinal tract.
The most common side effect is diarrhea.
The recommended dose is 10 g three times a day. Once normal serum potassium levels are achieved,
dose reduction is required to once a day (5–15 g). The preparation has 400 mg of sodium for every 5 g
dose. Hence, patients should be monitored for volume over load.
Potassium Preparation For Hypokalemia:
Oral potassium bicarbonate and citrate preparations exist. They can be used in patients with chronic
kidney disease who are prone to develop renal stones and have concomitant acidemia.
Oral potassium supplementation in peritoneal dialysis patients reduces mortality .
