Chronic kidney disease
Chronic kidney disease (CKD) refers to an irreversible deterioration in renal function which classically develops over a period of years.It starts as biochemical abnormalities, metabolic and endocrine functions of the kidney, then progress to clinical symptoms and signs of renal failure (uremia).
In end-stage renal disease or failure (ESRD or ESRF), death is likely without renal replacement therapy (RRT).
One half of CKD patients are above age 65 years.
Etiology
Common causes of ESRD are shown in Box 17.29.
Many patients diagnosed at a late stage have bilateral small kidneys.
17.29 Common causes of end-stage renal failure
DiseaseProportionCommentsCongenital and inherited5%Polycystic kidney dis, Alport's dis.Renal artery stenosis5%Hypertension5-20%Glomerular diseases10-20%IgA nephropathy is most commonInterstitial diseases20-30%Systemic inflamm diseases5-10%e.g. SLE, vasculitisDiabetes mellitus20-40%Large racial and geograph differncesUnknown5-20%
Clinical assessment
CKD presents as a raised B. urea and creatinine found during routine.
The great majority are asymptomatic until GFR falls < 30 mL/min/1.73 m2 (stage 4 or 5).
Thereafter, symptoms and signs: tiredness or breathlessness.
In ESRD (stage 5) there may be pruritus, anorexia, nausea and vomiting.
Later, hiccups, Kussmaul's (acidotic) respiration, muscular twitching, fits, drowsiness and coma.
STAGE 1; 2; 3
The majority of patients with CKD stages 1-3 will not develop ESRD.
Elderly patients (70 y), have a steep increase in the prevalence of CKD
Proteinuria, microalbuminuria or GFR < 50 are at increased Cardio-V risk.
Recommended investigations & management in stage 1 – 3 (Box 17.30) include:
BP control: →target 130/80 mmHg, and 125/75 mmHg in proteinuria. Use of ACEi or ARBs in those with proteinuria
Lipid management (statins)
Lifestyle advice: smoking, exercise, diet and weight.
Which patient, in stage 1 3, you will refer to a nephrologist?
Those who are likely to progress to ESRD:
Young age
CKD stage 4 (in the absence of other indications)
GFR fall > 5 in 1 year, or > 10 mL/min/1.73 m2 over 5 year
Proteinuria: PCR > 100 mg/mmol or ACR > 70 mg/mmol
Hematuria, may be a marker for inflammatory nephritis.
Investigation & management of progressive and stage 4+ CKD
The aim here is:-Identify the underlying renal disease where possible.
Identify reversible factors as UT-obstruction, hypotension, nephrotoxic drug.
Prevent further renal damage.
Limit the adverse effects of the loss of renal function (eg anemia, osteodystrophy, electrolyte imbalance etc.).
Address any associated cardiovascular risk/disease.
Institute renal replacement therapy, when appropriate.
17.30 Suggested investigations in chronic kidney disease
Initial tests
InterpretationUrea and creatinine
To assess stability/progression: compare to previous results
Urinalysis and proteinuria
Hematuria & proteinuria may i→ cause. Proteinuria →risk of progressive CKD requiring preventive ACEi or ARB therapyElectrolytesTo identify hyperkalemia and acidosisCa, PO4, parath-hormTo assess renal osteodystrophyAlbuminLow albumin: consider malnutrition, inflammationFull blood count ( Fe, ferritin, folate, B12)If anemic, exclude common non-renal explanations then manage as renal anemiaLipids, glucose HbA1cCardiovascular risk high in CKD: treat risk factors aggressivelyRenal ultrasoundTo exclude obstruction, Small kidneys suggest chronicityAsymmetric size suggests renovascular or development disease
Hepatitis & HIV serology
Before dialysis or transplant; also Hepatitis B vaccinationECG
If patient is > 40 yrs or ↑K, or risk factors for cardiac disease
Other tests
Relevant tests from in next Boxes, in CKD of unknown etiologyRetarding the progression of CKD
The rate of deterioration in renal function varies between patients but is relatively constant for an individual patient. A plot of GFR, or of the reciprocal of the plasma creatinine concentration against time (Fig. 17.18), predicts when dialysis will be required and detects any unexpected worsening of kidney disease. It can also be used to monitor the success of interventions.Control of blood pressure
Lowering BP slows progressionof CKD, independently of drug type.Various targets BP have been suggested: 130/80 mmHg for CKD alone, lowered to 125/75 mmHg for those with proteinuria > 1 g/day.
Proteinuria
There is a clear relationship between the degree of proteinuria and the rate of progression of renal disease, and strong evidence that reducing proteinuria reduces renal risk.
ACEi & ARBs are more effective at reducing proteinuria and retarding the progression of kidney disease.
ACEi also reduce cardiovascular events & all mortality in CKD.
ACEi and/or ARBs should be used in all patients with incipient or overt diabetic nephropathy or PCR > 50 mg/mmolwith or without hypertension.
17.31 Blood pressure lowering and progression of chronic kidney disease
'In an analysis of 20 randomised controlled trials, including over 50 000 patients with CKD, the risk of ESRD reduced as BP was lowered.The group with the highest reduction in blood pressure (-6.9 mmHg (95% CI -9.1 to -4.8)) had a relative risk of ESRD of 0.74 (0.59-0.92).
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17.32 Renin-angiotensin system blockade in chronic kidney disease
'ACE inhibitors and ARBs reduce proteinuria and slow the decline in GFR in both diabetic and non-diabetic patients with hypertension, CKD and proteinuria to a greater degree than that seen with blood pressure reduction alone.'
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Low-protein diets are difficult to adhere to & carry a risk of malnutrition.
Before approaching ESRD, no excess protein
During ESRD adequate intake of calories to prevent malnutrition.
Smoking cessation also slows the decline in renal function. Exercise and weight loss may reduce proteinuria.
Limiting the adverse effects of CKD
1- Fluid & electrolyte balanceFluid retention is common & fluid retention may lead to episodic pulmonary edema
Limit sodium intake (e.g. 100 mmol/day)& loop diuretics are often also required.
Salt-wasting' disease may require a high sodium and water intake. (cystic disease, obstructive uropathy, reflux nephropathy or other TI disease, but not GN
2- Anemia
Anemia is common; it usually correlates with the severity of kidney disease and contributes to many of the non-specific symptoms of CKD. Untreated, Hb can be 5 7 g/dl in CKD stage 5. Causes of anemia in CKD:
relative deficiency of erythropoietin
Toxic depression of bone marrow
reduced red cell survival
bleeding due to capillary fragility and poor platelet function
reduced dietary intake and absorption and utilisation of iron.
In patients with polycystic kidneys, anemia is less severe or absent. They may have persevered interstitial fibroblasts that secrete erythropoietin.
Recombinant human erythropoietin (rEPO) & other erythropoiesis-stimulating agents (ESAs) are effective in correcting the anemia of CKD and improve the associated morbidity. Their side effects are hypertension and thrombosis (e.g. of arteriovenous fistulas used for hemodialysis).
The target hemoglobin is usually between 10 – 12 g/L.
3- Hyperkalemia
Lecture 34- Acidosis
↓GFR → metabolic acidosis, which is often symptomatic in late stages.The plasma bicarbonate should be maintained > 22 mmol/L by giving sodium bicarbonate supplements (1 g 8-hourly).
The increased sodium intake →hypertension or edema; Ca carbonate (3 g/d) is an alternative that is also used to bind dietary phosphate.
5- Cardiovascular disease and lipids
CKD is an independent risk factor for occlusive cardiovascular disease.
Hypertension & atherosclerosis is common.
Arterial calcification → vascular rigidity & occlusion.
LVH is frequent in ESRD → arrhythmic deaths
Pericarditis is common in ESRD → tamponade & constrictive Pericarditis.
6- Hypercholesterolemia
↑cholesterol is universal in patients with significant proteinuria,
↑ triglyceride levels are common in CKD.
Statins → controls lipids in CKD & cardio-protective effect
7- Renal osteodystrophy
This metabolic bone disease which accompanies CKD consists of a mixture of osteomalacia, hyperparathyroid bone disease (osteitis fibrosa), osteoporosis and osteosclerosis (Figure 17.19 Davidson).Renal hydroxylation (1α) of vit D→ hypocalcemia → Osteomalacia.
↓ calcium, & ↑ phosphate → secondary hyperparathyroidism → osteitis fibrosa.
Tertiary hyperparathyroidism (autonomous) develops → hypercalcemia.
Secondary hyperparathyroidism is prevented by giving
1α-hydroxylated vitamin D in patients with hypocalcemia or high PTH
Calcimimetic agents can also ↓PTH via a direct action on the parathyroid glands.
In tertiary hyperparathyroidism, parathyroidectomy is sometimes required.
Hyperphosphatemia is controlled by: -
dietary restriction (milk, cheese, eggs. seeds, cola)
phosphate-binding drugs, they bind food phosphate, and prevent absorption, as: -
calcium carbonate
lanthanum carbonate
aluminium hydroxide, effective but is not used now because toxicity.
Polymer-based phosphate binders (Sevelamer).
Other adverse effects of ESRD
8- Immunity (cellular and humoral) → susceptibility to infection.
9- Bleeding tendency in ESRD → cutaneous ecchymoses & mucosal bleeds.
Platelet function is impaired and bleeding time prolonged.Adequate dialysis, partially corrects the bleeding.
10- Myopathy (Generalised) is due to a combination of poor nutrition,↑PTH, ↓vitamin D, electrolyte metabolism distrubance. Paitient may have muscle cramps, and 'restless leg syndrome', in which the patient's legs are jumpy during the night, may be troublesome.
11- Neuropathy may appear late in the course of CKD but may improve or even resolve once dialysis is established. It is :- sensory neuropathy may cause paresthesie, motor neuropathy may present as foot drop, and autonomic
12- Endocrine A number of hormonal abnormalities may be present.
↓ libido and sexual function, in part due to hyperprolactinemia.Decreased renal insulin catabolisim → ↑half-life of insulin → less insulin requirements & hypoglycemia. However, there is also relative insulin resistance.
13- Gastrointestinal: Anorexia, nausea and vomiting, and a higher incidence of peptic ulcer disease. H2-receptor antagonists or proton pump inhibitors are used.
Depression is common in CKD stage 4 & 5.
RENAL REPLACEMENT THERAPY
Dialysis is now routinely used in ARF & CRF, improves uremic toxins, electrolytes, acid-base status, body fluid volume. But do not replace the endocrine and metabolic of kidney functions.Renal replacement in acute renal failure
Indications in ARF:
Hyperkalemia: potassium > 6 mmol/L is hazardous.
Fluid overload and pulmonary edema.
Metabolic acidosis
B. urea > 30 mmol/L (180 mg/dL ) & S .creatinine > 600 μmol/L (6.8 mg/dL)
Uremic pericarditis/uremic encephalopathy.
The options for RRT in ARF are: - (see Davidson figure 17.20 ).
Hemodialysis (HD)
continuous arteriovenous hemofiltration(CAVHF)
continuous venovenous hemofiltration (CVVHF)
Peritoneal dialysis (PD)
Intermittent hemodialysis (HD)
It is efficient in clearance low molecular weight toxins (urea), to lesser degree middle MW toxins.
Complication of Hemodialysis
Fistula complications: - as thrombosis, infection, occlusion, aneurysm, subacute bacterial endocarditis (SBE), and large fistule may predispose to heart failure or angina in cardiac patient due to hyperdynamic circulation.
Dysequilibrium syndrome: - headache, confusion, seizures and coma, due to sudden change pH, electrolyte →brain edema. Prevention: The first session should be short.
Aluminum toxicity: - dialysate water or aluminum phosphate binders.
Mechanical complication as air embolism, blood leakage and thrombosis
Hypocomplementemia and hypersensitivity reaction due blood contact with the dialyzer.
Heparin complication: - as bleeding, Intracranial & GIT hemorrhage, osteoporosis.
Hyperlipidemia
Accelerated atherosclerosis
Hemofiltration (HF)
It is either intermittent or continuous, with 1-2 L/hour of filtrate replaced.
In CAVH, no blood pump, only arterial pressure drives blood to filter So there is poor filtration rates & clotting of the filter. (less used)
CVVH: there is blood pump → good pressure filtration. Needs long anticoagulation.
RRT in End-Stage Renal Disease (ESRD) (CKD stage 5)
All patients chosen for RRT are screened hepatitis B, hepatitis C. & HIV.RRT initiation, at S. creatinin 600-800 μmol/Lor an eGFR 8-10.
17.33 Comparison of hemodialysis and peritoneal dialysis
HemodialysisPeritoneal dialysis
Efficient
Less efficient
4 hrs three times/wk is usually adequate
4 exchanges/day → Chronic Ambulatory PD8-10 hrs/night→ Automated PD
2-3 days between treatmentsA few hours between treatmentsRequires visits to hospital Performed at homeRequires adequate venous circulation for vascular accessRequires an intact peritoneal cavity, no major scarring from previous surgerycompliance to diet & fluid restrictions Diet and fluid less restrictedFluid removal may cause BP instabilitySlow continuous fluid removal= asymptomaticVascular access infections may occurPeritonitis & catheter infections may occurPatients are usually dependent on othersPatients can take full responsibility for their Rx
Intermittent hemodialysis
Needs good blood supply, as AV fistula, which needs months.Needs heparin
Hemodialysis is usually carried out for 3-5 hours 3 times/w.
The dialysis 'dose' required is urea reduction ratio > 65%.
Plasma urea & creatinine are lowered, but do not return to normal.
Daily dialysis & longer (nocturnal) dialysis → better fluid & electrolyte control.
Dialyze the small molecular weight toxins & a little of middle MW toxins
Hemodiafiltration
Has a large pore membrane to clear both small & middle molecule.It is more expensive and long-term benefits are not yet established.
Peritoneal dialysis (PD)
Continuous ambulatory peritoneal dialysis (CAPD) involves insertion of a permanent catheter into the peritoneal cavity.
Two litres of sterile, dialysis fluid are introduced and left in for 6h. Then drained & replaced by fresh dialysis fluid, four-times-daily cycle.
In case of volume overload, hyper-osmolar fluid is used, to keep osmotic gradient & ultrafiltration occurs and the drained.
Here, the patient is mobile & able to undertake normal daily activities.
CAPD is useful in young children, & in elderlies with CV-disease. Its long-term use may be limited by episodes of bacterial peritonitis & damage to the peritoneal membrane
The use of automated peritoneal dialysis (APD) is now widespread. This system is similar to CAPD but uses a mechanical device to perform the fluid exchanges during the night, leaving the patient free, or with only a single exchange to perform, during the day.
17.35 Problems with continuous ambulatory peritoneal dialysis (CAPD)
Catheter exit site infectionUltrafiltration failure
Peritoneal membrane failure to transport (pores damage)
Sclerosing peritonitis
17.36 Renal replacement therapy in old age
Better life quality with RRT and age is NOT a barrier for RRT.Coexisting CVD→ intradialysis hypotension & pulmonary edema between sessions.
Survival on HD: difficult to predict, depends on age & co-morbid state.
Withdrawal from HD: a common cause of death elderly with comorbid disease.
Transplantation: Age is relative contraindication for transplantation.
Conservative therapy: i.e. without dialysis but with adequate support.
Renal transplantation (RTx)
RTx offers the best chance of:-
long-term survival
complete rehabilitation
most cost-effective Rx in ESRD.
It can restore normal kidney function
All ESRD are considered for Rx unless there is contraindications .
Kidney grafts may be taken from a cadaver or from a living donor.
ABO (blood group)
The degree of matching for major histocompatibility (MHC) antigens, particularly HLA-DR, influences the incidence of rejection.
Donor vessels are anastomosed to the recipient iliac artery and vein, and the donor ureter to the bladder.
Rtx require regular life-long monitor renal function & immunosuppression.
Immunosuppressive
A common regimen is triple therapy with prednisolone, ciclosporin or tacrolimus, and azathioprine or mycophenolate mofetil.
Rapamycin is an alternative that can be introduced later.
Complications of immunosuppression include infections and malignancy
Approximately 50% of whites develop skin malignancy by 15y.
17.37 Contraindications to renal transplantation
Absolute
Active malignancy: a period of at least 2 yrs of complete remission
Active vasculitis or recent anti-GBM disease
Severe heart disease
Severe occlusive aorto-iliac vascular disease
Relative
Age: very young children (< 1 yr) or older people (> 75 yrs)
High recurrence risk of native kidney disease in the transplant kidney (FSGN & MPGN)
Impaired bladder function, here an ileal conduit may be considered
Significant comorbidity