CKD

 

• Background

  Definition

  • Long-term haematuria or proteinuria, or...
  • GFR <60 for >3 months.

  Epidemiology

  • UK prevalence: 10%, mainly stage 1-3.
  • UK prevalence of renal replacement therapy (RRT i.e. dialysis or transplant): 1 in 1000. Commoner in men, with median onset in 60s.

  Stages

  1. GFR >90: no impairment.
  2. GFR 60-89: mild impairment.
  3. GFR 30-59: moderate impairment. Divided into 3a (45-59) and 3b (30-44).
  4. GFR 15-29: severe impairment.
  5. GFR <15 or on dialysis: kidney failure aka end-stage kidney disease (ESKD).
  • Based on 2 GFR readings 3 months apart.
  • Stage 1-2 also require the presence of kidney damage: persistent proteinuria or unexplained haematuria, structural disease, or glomerulonephritis.
  • Also known as stages G1-5.

  Causes

  Causes of new cases of RRT (UK 2013):

  • Diabetes is commonest (25%).
  • Glomerulonephritis is 2nd (15%), but the commonest cause of prevalent cases (20%).
  • Hypertension, PCKD, and pyelonephritis each account for 7%.
  • Others: idiopathic (15%), obstructive uropathy, renal vascular disease, SLE, amyloidosis.

• Signs and symptoms

  Earlier stages

  G1-4 is usually asymptomatic.

  Clinical signs that are present are usually attributable to their primary renal disease, including:

  • Diabetes: proteinuria and glycosuria on dipstick.
  • Glomerulonephritis: proteinuria and haematuria on dipstick, nephrotic syndrome.
  • Non-renal features e.g. hypertension.

  Later stages

  BROKEN PIDDLE BAGS:

  • ↑BP: fluid retention, ↑renin.
  • ↓RBCs (anaemia): ↓EPO, bleeding (in part due to ↓PLT).
  • Oedema: peripheral and periorbital. Pleural effusions.
  • K+ Elevation.
  • Neurological symptoms: peripheral polyneuropathy, restless legs, confusion, seizures, coma.
  • Pericarditis
  • Itch
  • Dermal darkening: skin pigmentation.
  • Diuresis: polyuria (especially nocturia) due to impaired urine concentration in later disease. Normal urine output in most patients.
  • Lipid Elevation.
  • Bone disease: initially asymptomatic, later bone pain, fractures, proximal muscle weakness.
  • Acidosis
  • GI: nausea, vomiting, diarrhoea, anorexia.
  • Skinny: weight loss.

  The commoner symptoms are fatigue (from anaemia or uraemia), oedema, nausea, anorexia, and pruritus.

• Investigations

  Screening and monitoring

  Screen for CKD using ACR and eGFR in those with the following risk factors:

  • Vascular: diabetes (annual), hypertension, CVD.
  • Structural disease: stones, prostate enlargement.
  • AKI, and 2-3 years post-event.
  • Multisystem disease with potential kidney involvement e.g. SLE.
  • Family history of end-stage kidney disease.
  • Opportunistic/incidental detection of haematuria. Rule out UTI first.
  • Long-term nephrotoxic drugs (annual screen): NSAIDs, lithium, cyclosporin, tacrolimus.

  Urine albumin:creatinine ratio (ACR):

  • Proteinuria (albuminuria) is ACR >3 mg/mmol.
  • ACR is more sensitive than protein:creatinine ratio (PCR) at lower protein levels, though their associations with CKD complications are similar.
  • In addition to the GFR stages (G1-5), NICE recommend classifying CKD by ACR: A1 mild (<3 mg/mmol), A2 moderate (3-30 mg/mmol), A3 severe (>30 mg/mmol). Both GFR and ACR independently predict risk of complications.

  Monitor progression of CKD using ACR and eGFR in CKD:

  • G1-3 and A1-2: annual testing.
  • Later stages: 3-6 monthly testing.

  Further investigations

  Bloods:

  • FBC: normocytic ↓Hb (common), ↓PLT (rare).
  • U+E: ↑urea, ↑creatinine, ↓Na+ or ↑Na+, ↑K+.
  • Monitor for ↓Ca2+, ↑PO43-, and ↑PTH if GFR <30.
  • Glucose: check for diabetes.
  • Lipids: may be elevated, especially TG.
  • Blood gas: metabolic acidosis.
  • Immunological: ANA, ANCA, anti-GBM, complement.
  • Serum and urine protein electrophoresis for myeloma.

  Kidney US:

  • Indications: accelerated progression, persistent haematuria, obstructive symptoms, family history of PCKD, GFR <30, pre-biopsy.
  • Possible findings: small kidneys, hydronephrosis (obstruction), stones.
  • Follow up with CT if masses or cysts detected.

  Biopsy:

  • Indicated if likely to affect treatment e.g. glomerulonephritis

• Management

  Overview:

  • For early stages, mainly about managing risk factors and reducing complications.
  • Counsel and educate patients about CKD, including that most with mild CKD will not progress to dialysis.
  • Most CKD managed by GP. Nephrology referral for severe/complicated disease or accelerated progression. Urology referral for suspected obstruction.
  • Severe/complicated disease is defined as G4-5 or A3, haematuria and proteinuria, resistant hypertension, suspected genetic cause, or renal artery stenosis.
  • Accelerated progression is defined as {GFR ↓25% and change in category} or {GFR ↓15 ml/min} in 1 year.

  Managing risk factors for progression

  Hypertension:

  • Treat to reduce pressure on remaining glomeruli.
  • ACEi or ARB 1st line (CCB 2nd line) in diabetes, ACR >30 with hypertension, or ACR >70. Otherwise, treat as per usual guidelines e.g. CCB 1st line if age >55.
  • Aim 140/90 normally, or 130/80 if diabetes or ACR >70.
  • ACEi also have specific renoprotective effects, including prevention and reversal of microalbuminuria.
  • Na+ and fluid restriction may help in later stages.

  Bone protection:

  • Bisphosphonates for G1-3.
  • Vitamin D (cholecalciferol [D3] or ergocalciferol [D2]) only if deficient.

  Others:

  • Statins for all. Aim for 40% non-HDL cholesterol reduction.
  • CVD prevention: weight loss, exercise, smoking cessation.
  • Urological intervention for obstruction.

  Drug contraindications and cautions:

  • Minimize prolonged NSAID use and/or monitor GFR closely.
  • Avoid: tetracyclines, nitrofurantoin, lithium, metformin, radiocontrast.
  • Reduce dose: β-lactams, aminoglycosides, digoxin, atenolol, LMWH, furosemide, opioids.

  Specific treatments

  Medical

  Bone disease:

  • If there is bone disease despite vitamin D correction, and GFR <30, offer active vitamin D metabolites – calcitriol or alfacalcidol – which do not require renal hydroxylation.
  • ↑PO43-: dietician referral for low PO43- diet and offer phosphate binders (calcium acetate, calcium carbonate, aluminium hydroxide, sevelamer).

  Others:

  • ↑K+: low K+ diet, exchange resins to treat.
  • Anaemia: iron (PO initially if not on dialysis, IV if on dialysis or PO unsuccessful), recombinant EPO if anaemic despite being iron replete (aim Hb 100-120 g/L).
  • Sodium bicarbonate if serum bicarb levels <20 mmol/L.
  • Fluid overload: loop diuretics, fluid restriction.

  Renal replacement therapy (RRT)

  • Should be considered in all patients with G5 or uraemia.
  • Options: dialysis or kidney transplant.

• Complications

  • CVD: CKD is an independent risk factors for CVD, which is the commonest cause of death in the disease. Risk is reduced by transplantation.
  • LVH due to anaemia and hypertension.
  • Infection due to CKD itself, dialysis access sites, or immunosuppression post-transplant.

• Dialysis

  Definition

  Diffusion is the movement of molecules from high to low concentration areas. Dialysis is when this diffusion occurs across a membrane.

  Mechanism

  • Passage of blood on one side of a semi-permeable membrane, with dialysate going the opposite direction on the other side. This counter current ensures that a constant concentration gradient is maintained.
  • Membrane can be artificial (haemodialysis, HD) or the peritoneum (PD).
  • Dialysate contains electrolytes and buffer, with solutes moving across membrane via concentration gradient.
  • Corrects electrolyte levels (e.g. dialysate contains low K+ and PO43- to draw it from blood), fluid levels, and filters toxins such as urea.
  • Amount of water removed can be affected by controlling pressure (haemodialysis only) and dialysate osmolality (e.g. with glucose).
  • The removal of fluid using pressure during HD is known as ultrafiltration. Unlike haemofiltration, this is purely to reduce fluid overload and plays only a negligible role in solute removal. However, haemofiltration can be combined with dialysis, in haemodiafiltration, to achieve removal of larger molecular weight solutes.

  Indications in CKD

  • Consider in all patients with stage 5 CKD.
  • Usually started when symptomatic (e.g. uremia, refractory fluid overload) or eGFR 5-7, with assessement beginning at least 1 year before expecting to reach this stage.

  Haemodialysis

  Blood drawn out of body and run past dialysate.

  Pros:

  • Access can be temporary: catheter in IJV, subclavian vein, or femoral vein. Can be tunnelled, reducing the risk of infection and thus increasing durability from days to months.
  • Permanent access is preferred, providing ↑blood flow and ↓infection risk. Options are radial or brachial AV fistula, or upper arm or leg graft. The purpose of an AV fistula is to dilate a vein to allow repeated cannulation; this is achieved by forming an anastomosis between an artery and vein, leading to arterialization of the vein over 4-6 weeks.

  Cons:

  • Usually in hospital: 3 x 4 hrs/week.
  • Risk of sepsis.
  • Risk of fistula failure from thrombosis, stenosis, aneurysm, or infection. To help preserve it, venepuncture and cannulation should not be performed on the same arm for any purpose but dialysis.
  • Requires strict fluid and potassium restriction.
  • Leads to growth restriction in kids.

  Peritoneal dialysis

  Mechanism:

  • Permanent Tenckhoff catheter in peritoneum fitted under general anaesthesia.
  • Dialysate fills peritoneal cavity, exchanges solutes with vessels between the subcutaneous fat and parietal peritoneum, then is removed.
  • Can be continuous ambulatory dialysis – several session with new bags during day – or automated nocturnal dialysis with multi-bag machines.

  Pros:

  • Usually done at home.
  • Good for kids as less growth restriction than haemodialysis.
  • Less rigorous dietary and fluid restrictions than haemodialysis.

  Cons:

  • Risk of peritonitis or exit site infection, commonly Staph. epidermidis. Safer than temporary haemodialysis, but less safe than permanent haemodialysis.
  • Cannot be used if there are abdominal problems e.g. adhesions, obesity, GI disease.
  • Metabolic side effects: ↑glucose, fluid retention.

  Patient choice

  • Dialysis prolongs life and reduces CKD complications, but symptom control is not brilliant and treatment is very burdensome.
  • Individuals often reasonably opt for conservative management instead of dialysis, and so you should just continue usual management.
  • Patient choice should also guide decision of haemodialysis vs. peritoneal. Ability for self-care may affect choice.
  • Peritoneal should be offered as first choice if age <2, significant comorbidities, or there is residual renal function.

• Kidney transplantation

  Benefits

  • Improves symptoms and improves quality of life significantly more than dialysis.
  • Cheaper than 1 year of dialysis.
  • Average survival time of organ is around 10 years. Better if living donor.

  Patient and donor selection

  Considered for all patients with stage 5 CKD, but active malignancy is a contraindication.

  Donors:

  • Can be live or cadaveric donations, the former often family members.

  Matching:

  • ABO: must match.
  • HLA: comprising -A, -B, -C, and -DR. Ideally match all 8 (2 alleles each), with -DR the most important.

  Procedure

  • Pre-transplant blood transfusion reduces rejection.
  • Aim to minimize warm ischaemic time of organ.
  • Graft is heterotopic, usually in the RIF, with the old kidney left in place unless it is causing mass symptoms. The renal vein is anastomosed to the external iliac vein, and the renal artery anastomosed to the external iliac artery.

  Post-op management

  Short-term

  Catheterise for 5 days to monitor urine output and protect bladder anastomosis.

  Long-term

  Post-transplant, most patients are on triple immunosuppression:

  • Calcineurin inhibitor: tacrolimus or ciclosporin. Prescribe by brand and monitor trough levels.
  • Steroids
  • Antimetabolite: azathioprine or MMF.

  Other drugs:

  • Aspirin, as CVD is the commonest cause of death in transplant patients.
  • Antimicrobial prophylaxis.

  Complications

  Rejection:

  • Hyperacute: on the operating table, due to pre-formed antibodies, leading to rapid organ death. Uncommon.
  • Acute: weeks to months post-transplant. Mainly T-cell mediated. May present with fever and kidney tenderness and swelling. Common and treated with high-dose immunosuppression, which may reverse it.
  • Chronic: gradual decline in renal function years later, often linked to vascular fibrosis.

  Urological and vascular:

  • Ureteric obstruction or anastomotic leak.
  • Renal artery thrombosis. Early but rare.
  • Renal artery stenosis.

  Lymphocele:

  • Lymphatic collection around transplanted kidney.
  • Causes mass effect, leading to impaired graft function and unilateral leg swelling.
  • Affects 20%, usually 2 weeks to 6 months post-surgery.

  Side effects of immunosuppression:

  • Infection: CMV (1-6 months), EBV (>6 months), BK, fungi.
  • Calcineurin inhibitors: GI (nausea, vomiting, abdo pain), kidney and liver toxicity, HTN, ↑cholesterol, ↑K+, tremor, ↑glucose, lymphoma or skin cancer.
  • Ciclosporin-specific: hypertrichosis, gum hyperplasia.
  • Tacrolimus-specific: lung disease (fibrosis, effusions), PUD, cytopaenia (↓RBC, ↓WBC, ↓PLT), neurotoxicity (mood changes, confusion, seizures), tinnitus and hearing loss.

• Pathophysiology of kidney failure

  Phases and progression

  • Initial injury → progressive decline, with ↓GFR and ↑creatinine → established kidney failure.
  • Progression is due to persistence of initial injury, or ↑strain on remaining healthy glomeruli.
  • Accelerated by various factors including hypertension, proteinuria, ↑lipids, UTI or systemic infection, medication, and pregnancy.

  Pathophysiological changes

  • Fluid retention due to Na+ retention and protein loss. Na+ can also be lost due to tubular damage.
  • Failure to excrete products of protein metabolism, including uraemic toxins.
  • Failure to excrete K+, H+, and PO43-.
  • ↓EPO synthesis.
  • ↑Renin: complex mechanism involving endothelial dysfunction and changes in renal haemodynamics.
  • ↓Vitamin D and ↓Ca2+: failure of renal conversion of calcidiol to the active calcitriol (aka 1,25 (OH) vit D) by 1-α-hydroxylase, leading to ↓Ca2+ absorption. Secondary ↑PTH results. ↓Ca2+ and ↑PTH are exacerbated by ↑PO43-.
  • ↑Lipids, mainly triglycerides, due to ↓lipoprotein lipase. Mechanism unclear.
  • ↑Infection risk: various mechanisms, including urinary loss of immune-related proteins.

  Renal bone disease

  Aka renal osteodystrophy, or CKD mineral and bone disorder.

  A combination of:

  • Osteomalacia: ↓vitamin D → ↓Ca2+.
  • Osteitis fibrosa cystica: ↑PTH → ↑osteoclast activity causing bone resorption.

  Uraemic syndrome

  • A group of symptoms associated with the accumulation of uraemic toxins, a general term for various solutes retained due to renal impairment. The exact mechanism of most symptoms is unclear.
  • Uraemic toxins include urea, homocysteine, phenols, and β2-microglobulin.
  • Symptoms include malaise, central (uraemic encephalopathy) and peripheral neurological disease, pericarditis, GI symptoms, thrombocytopaenia, and skin changes.

• Polycystic kidney disease

  Pathophysiology and genetics

  Pathophysiology:

  • Multiple kidney cysts which grow and compress kidney architecture and vasculature, compromising function. Predisposes to stones, haemorrhage, colic (from thrombosis), and UTIs.
  • Extrarenal manifestations: hepatic cysts (80%), pancreatic cysts, aortic root dilation and aneurysm, mitral prolapse and regurgitation, abdominal wall hernias, intracranial aneurysms (10%).

  90% are autosomal dominant (ADPKD):

  • Usually PKD1 mutation (85%) which encodes the membrane protein polycystin 1.
  • Median onset of end-stage kidney disease (ESKD) in 50s, but in 70s with the rarer PKD2 mutation.
  • Main focus of this section.
  • UK prevalence: 1 in 1000.

  10% are autosomal recessive (ARPKD):

  • Characterised by kidney cysts beginning in collecting duct, and hepatic fibrosis with portal hypertension.
  • Childhood onset (<5 years) and may even be congenital (and fatal).
  • Most need renal replacement therapy by age 20.
  • UK prevalence: 1 in 10,000

  Clinical features

  • Flank pain (>50%). Due to cysts, or secondary to stones, haemorrhage, or UTI.
  • Haematuria (micro or macro), nocturia.
  • Hypertension is common, and may be the presenting complaint.
  • Renal signs: large, palpable kidneys.
  • Extrarenal signs: hepatomegaly, murmurs, abdominal hernias.

  Investigations

  Diagnosis:

  • Kidney US: {≥2 cysts either side if age <30, ≥2 bilaterally if 30-59, ≥4 bilaterally if ≥60} plus {family history of PKD or ESKD}.
  • Without family history, needs bilateral cysts and enlargement, or hepatic cysts.
  • CT or MRI if US unclear, then genetic testing if still unclear.

  Other tests:

  • Urinalysis
  • Bloods: U+E, FBC (may be ↑Hb due to ↑EPO).
  • Extrarenal tests: ECG and echo in suspected heart disease, head CT in acute headache.

  Management

  • Annual US, BP, and kidney function tests.
  • ACEi or ARBs, aiming for BP <130/80.
  • In medically refractory abdo/loin pain, cysts can be aspirated under CT guidance.
  • Renal replacement therapy for ESKD.
  • Screening is not routinely done for asymptomatic children; it should be their own choice in adulthood. However, can check BP as it may rise early.

  Complications

  • CKD and ESKD.
  • CVD: hypertension, LVH, valve disease.
  • Ruptured intracranial aneurysm e.g. sub-arachnoid haemorrhage.