CKD Complications and Treatment

Anaemia of CKD

Anaemia is a cardinal complication of chronic kidney disease (CKD), typically emerging when estimated GFR falls below approximately 60 mL/min/1.73 m² and becoming progressively more prevalent in CKD stages 4–5. It is classically normocytic, normochromic, hypoproliferative, with an inappropriately low reticulocyte count for the degree of anaemia. In MRCP questions, the key is to distinguish erythropoietin deficiency from iron deficiency, inflammation, occult blood loss, haemolysis, B₁₂/folate deficiency, marrow disease, and drug-related causes.

Pathophysiology

The dominant mechanism is reduced renal production of erythropoietin by peritubular interstitial fibroblast-like cells in the renal cortex and outer medulla. However, CKD anaemia is multifactorial. Uraemic toxins reduce erythroid progenitor responsiveness, shorten red cell survival from the normal 120 days to approximately 60–90 days, and impair platelet function, increasing occult bleeding risk. Chronic inflammation increases hepatic hepcidin, which degrades ferroportin and reduces duodenal iron absorption and macrophage iron release, causing functional iron deficiency. Dialysis patients may lose 1–3 g iron/year through circuit losses, blood sampling and access-related bleeding.

Mechanism	Typical laboratory pattern	Exam relevance
Erythropoietin deficiency	Normocytic anaemia, low reticulocytes	Most characteristic mechanism in CKD stages 3b–5
Absolute iron deficiency	Low ferritin, low TSAT, microcytosis may occur	Consider GI blood loss, especially if disproportionate
Functional iron deficiency	Normal/high ferritin, low TSAT	Common with inflammation and ESA therapy
Inflammation/malnutrition	High CRP, high ferritin, ESA hyporesponsiveness	Avoid escalating ESA without addressing cause
Hyperparathyroidism/aluminium toxicity	Marrow fibrosis or microcytosis	Classically causes ESA resistance

Definitions and investigation

KDIGO defines anaemia in adults with CKD as haemoglobin <130 g/L in men and <120 g/L in women. Evaluation should include FBC with indices, reticulocyte count, ferritin, transferrin saturation (TSAT), B₁₂, folate, CRP, haemolysis screen if indicated, and assessment for blood loss. Anaemia should not be attributed to CKD solely because CKD is present; a rapid fall in haemoglobin, macrocytosis, pancytopenia, haematuria, or iron deficiency mandates further investigation.

Parameter	Interpretation in CKD anaemia	Useful thresholds
Ferritin	Iron stores; acute-phase reactant	Absolute deficiency often <100 micrograms/L in non-dialysis CKD; <200 micrograms/L in haemodialysis
TSAT	Circulating iron availability	Iron therapy usually considered if TSAT ≤30% and ferritin ≤500 micrograms/L
Reticulocytes	Marrow response	Usually inappropriately low
MCV	Usually normal	Microcytosis suggests iron deficiency/aluminium; macrocytosis suggests B12, folate, alcohol, drugs or MDS

Treatment strategy

Management proceeds in sequence: correct reversible causes, optimise iron status, then consider erythropoiesis-stimulating agents (ESAs). Transfusion is avoided where possible, particularly in transplant candidates, because it increases HLA sensitisation and may delay transplantation. It remains appropriate for life-threatening anaemia, acute bleeding, unstable coronary disease, or when ESA therapy is ineffective or inappropriate.

Iron therapy

Iron deficiency should be corrected before and during ESA therapy. Oral iron, for example ferrous sulfate 200 mg two to three times daily or equivalent, is inexpensive but frequently limited by gastrointestinal intolerance, poor adherence and impaired absorption from inflammation, phosphate binders and proton pump inhibitors. Intravenous iron is preferred in haemodialysis and often in advanced CKD or ESA-treated patients. Common regimens include iron sucrose 100–200 mg per dose, ferric derisomaltose up to 20 mg/kg, or ferric carboxymaltose typically 500–1000 mg per infusion, depending on product licence and local protocol.

The PIVOTAL trial in haemodialysis patients showed that proactive high-dose IV iron, given unless ferritin exceeded 700 micrograms/L or TSAT exceeded 40%, reduced the composite of death, myocardial infarction, stroke or heart failure hospitalisation compared with reactive low-dose iron, without excess infection signal. This supports modern practice of avoiding under-replacement in dialysis patients.

Erythropoiesis-stimulating agents

ESAs are considered when haemoglobin is persistently around <100 g/L after iron repletion and other causes have been addressed, individualising for symptoms, rate of fall, cardiovascular disease and transfusion risk. Targeting normal haemoglobin is harmful. KDIGO and NICE-aligned practice generally aims for a maintenance haemoglobin around 100–120 g/L, avoiding intentional rises above 130 g/L.

Agent	Typical dosing concept	Approximate half-life	Comments
Epoetin alfa/beta	50–100 units/kg subcutaneously or IV 1–3 times weekly	IV 4–13 h; SC longer functional effect	Short-acting; titrate no more often than every 2–4 weeks
Darbepoetin alfa	0.45 micrograms/kg weekly or every 2 weeks	~25 h IV; ~48 h SC	Longer acting via increased sialylation
Methoxy polyethylene glycol-epoetin beta	Often every 2–4 weeks	~130 h	Continuous erythropoietin receptor activator

Adverse effects include hypertension, vascular access thrombosis, seizures rarely during rapid haemoglobin rise, and increased thromboembolic and cardiovascular events when high haemoglobin targets are pursued. ESA hyporesponsiveness is defined pragmatically by failure to achieve target haemoglobin despite appropriate dosing, or a need for repeated dose escalation; causes include iron deficiency, infection, inflammation, underdialysis, hyperparathyroidism, malnutrition, ACE inhibitor/ARB effect, malignancy and marrow disease.

Landmark evidence

Several trials explain why “normalisation” of haemoglobin is avoided. In CHOIR, targeting haemoglobin 135 g/L rather than 113 g/L in non-dialysis CKD increased the composite risk of death, myocardial infarction, heart failure hospitalisation and stroke. CREATE showed no cardiovascular benefit from early complete correction. TREAT, using darbepoetin in diabetic CKD, found no reduction in major cardiovascular or renal outcomes but approximately doubled stroke risk. Thus, examination answers should favour symptom-guided partial correction, iron optimisation, and conservative ESA targets rather than aggressive normalisation.

Mineral Bone Disease

Definition and pathophysiology

CKD–mineral and bone disorder is a systemic disorder of mineral metabolism in CKD manifested by biochemical abnormalities, bone turnover/mineralisation defects, and extra-skeletal calcification. It becomes clinically important from CKD G3a and is almost universal by G5D. KDIGO frames CKD-MBD as abnormalities of calcium, phosphate, parathyroid hormone, vitamin D, FGF23, bone turnover, bone volume, mineralisation, growth, and vascular or soft-tissue calcification.

The earliest adaptive response to declining nephron mass is increased fibroblast growth factor 23 from osteocytes, driven by phosphate retention and reduced calcitriol. FGF23 suppresses proximal tubular sodium-phosphate cotransporters and inhibits 1α-hydroxylase, lowering 1,25-dihydroxyvitamin D. This reduces intestinal calcium absorption, promotes relative hypocalcaemia, and stimulates secondary hyperparathyroidism. Persistent hyperphosphataemia, skeletal resistance to PTH, reduced calcitriol, and parathyroid gland hyperplasia lead to high-turnover bone disease. In late disease, autonomous nodular parathyroid hyperplasia may produce tertiary hyperparathyroidism, usually with hypercalcaemia.

Parameter	Typical reference range	CKD-MBD interpretation
Phosphate	0.8–1.5 mmol/L	Persistent elevation predicts mortality and vascular calcification; treat trends rather than isolated results
Adjusted calcium	2.2–2.6 mmol/L	Avoid hypercalcaemia; albumin correction is imprecise in uraemia, acidosis, and critical illness
Intact PTH	Assay-dependent, often 1.6–6.9 pmol/L	Interpret with phosphate, calcium, alkaline phosphatase, CKD stage, and serial trend
25-hydroxyvitamin D	Sufficiency commonly >50 nmol/L	Deficiency should be corrected as in the general population

Classification of renal osteodystrophy

Renal osteodystrophy is the bone component of CKD-MBD and is classified histologically by the TMV system: turnover, mineralisation, and volume. Bone biopsy with tetracycline labelling is the gold standard but is reserved for unexplained fractures, persistent bone pain, unexplained hypercalcaemia or hypophosphataemia, suspected aluminium toxicity, or before antiresorptive therapy when the turnover state is uncertain.

Lesion	Turnover	Mineralisation	Typical associations
Osteitis fibrosa cystica	High	Variable	Severe secondary hyperparathyroidism; subperiosteal resorption, “salt and pepper” skull
Adynamic bone disease	Low	Normal	Diabetes, elderly patients, calcium loading, excessive vitamin D analogues, low PTH
Osteomalacia	Low/normal	Defective	Vitamin D deficiency, aluminium exposure, severe hypophosphataemia
Mixed uraemic osteodystrophy	High	Defective	Combined hyperparathyroidism and impaired mineralisation

Monitoring and treatment targets

KDIGO 2017 recommends monitoring serum calcium, phosphate, PTH, and alkaline phosphatase from CKD G3a. Approximate intervals are: G3a–G3b every 6–12 months for calcium/phosphate and PTH according to baseline; G4 every 3–6 months; G5/G5D every 1–3 months for calcium/phosphate and every 3–6 months for PTH. In dialysis patients, PTH is generally maintained at approximately 2–9 times the assay upper reference limit; marked movement within this range should prompt therapy adjustment. In non-dialysis CKD, there is no single PTH target: evaluate progressively rising or persistently elevated PTH for hyperphosphataemia, hypocalcaemia, high phosphate intake, and vitamin D deficiency.

Management

Treatment is directed at reducing phosphate burden, avoiding calcium loading, preventing severe hyperparathyroidism, and avoiding oversuppression causing adynamic bone disease. Dietary phosphate restriction usually targets 800–1000 mg/day, prioritising avoidance of inorganic phosphate additives, which are highly absorbable. Protein restriction must be balanced against malnutrition risk, particularly in advanced CKD and dialysis.

Therapy	Typical adult dose	Key adverse effects/exam points
Calcium carbonate/acetate	With meals; limit elemental calcium commonly to ≤1500 mg/day and total intake ≤2000 mg/day	Avoid or restrict with hypercalcaemia, vascular calcification, adynamic bone disease, or low PTH
Sevelamer carbonate	800–1600 mg three times daily with meals	Non-calcium binder; GI upset; may lower LDL; useful when calcium loading undesirable
Lanthanum carbonate	500–1000 mg three times daily with meals	Chewable; nausea; radiopaque; avoid overinterpreting abdominal radiographs
Sucroferric oxyhydroxide	500 mg three times daily with meals, titrated	Lower pill burden; dark stools, diarrhoea; monitor iron indices if using iron-based binders
Alfacalcidol/calcitriol	Alfacalcidol 0.25 micrograms daily or alternate days; calcitriol 0.25 micrograms daily, titrated	Suppress PTH but increase calcium and phosphate; not routine in CKD G3a–G5 unless severe progressive hyperparathyroidism
Cinacalcet	30 mg once daily, titrate every 2–4 weeks to 60–180 mg/day	Calcimimetic; lowers PTH and calcium; nausea, hypocalcaemia; mainly G5D
Etelcalcetide	5 mg IV three times weekly after haemodialysis, titrate 2.5–15 mg	Useful adherence advantage in haemodialysis; hypocalcaemia and QT concerns if severe

Landmark evidence is nuanced. The EVOLVE trial in haemodialysis patients with moderate-to-severe secondary hyperparathyroidism did not significantly reduce the unadjusted composite cardiovascular endpoint with cinacalcet in intention-to-treat analysis (hazard ratio approximately 0.93; p=0.11), although adjusted and age-stratified analyses suggested possible benefit. Trials of non-calcium binders such as sevelamer show less hypercalcaemia and slower calcification progression in some cohorts, but hard mortality advantages are inconsistent; hence guidelines emphasise individualisation rather than rigid phosphate “normalisation” at all costs.

Parathyroidectomy is indicated for severe hyperparathyroidism refractory to medical therapy, especially with persistent very high PTH, hypercalcaemia or hyperphosphataemia, bone pain, fractures, pruritus, calciphylaxis, or soft-tissue calcification. Post-operatively, anticipate hungry bone syndrome with profound hypocalcaemia requiring high-dose calcium and active vitamin D replacement.

Dialysis

Dialysis is renal replacement therapy that substitutes principally for excretory and volume-regulatory renal functions; endocrine functions require separate treatment. Solute removal occurs by diffusion down a concentration gradient, convection with solvent drag, and ultrafiltration driven by transmembrane or osmotic pressure. Small solutes such as urea and potassium are diffusion-dominant, whereas larger “middle molecules” such as β₂-microglobulin are better cleared by high-flux membranes and convective techniques.

Indications and Timing

In established CKD, dialysis should be initiated for symptoms or refractory biochemical/volume complications, not an arbitrary eGFR alone. NICE and KDIGO practice is to plan access and education by CKD G4–G5, and consider initiation when eGFR is approximately 5–10 mL/min/1.73 m² if accompanied by uraemic symptoms, malnutrition, refractory hyperkalaemia, acidosis, fluid overload, or serositis. The IDEAL trial showed no survival benefit from early start at eGFR 10–14 versus late start at 5–7 mL/min/1.73 m², supporting symptom-led initiation.

Urgent indication	Typical threshold/context
Hyperkalaemia	K+ usually ≥6.5 mmol/L, ECG changes, or refractory to temporising therapy
Metabolic acidosis	Severe/refractory, often pH <7.1–7.2 despite bicarbonate where appropriate
Fluid overload	Pulmonary oedema or uncontrolled hypertension despite maximal diuretics
Uraemic complications	Pericarditis, encephalopathy, seizures, bleeding diathesis, severe pruritus or anorexia/cachexia
Toxins	Dialysable poisons: lithium, methanol, ethylene glycol, salicylate, severe metformin-associated lactic acidosis

Haemodialysis

Conventional haemodialysis is typically prescribed 3 times weekly for 3.5–5 hours, with blood flow 300–500 mL/min and dialysate flow 500–800 mL/min. Dialysate sodium is usually 138–140 mmol/L, bicarbonate 32–38 mmol/L, calcium 1.25–1.5 mmol/L, and potassium individualised, commonly 1–3 mmol/L. Ultrafiltration should avoid excessive rates; observational data associate rates >10–13 mL/kg/hour with intradialytic hypotension and mortality.

Adequacy is assessed by urea kinetic modelling. Single-pool Kt/V is the standard measure: K is dialyser urea clearance, t time, V urea distribution volume. A common target is spKt/V ≥1.2 per session for thrice-weekly HD, with delivered weekly standard Kt/V broadly ≥2.0. Urea reduction ratio should generally be >65%. Increasing dose beyond conventional adequacy did not improve survival in the HEMO trial, although high-flux dialysis reduced β₂-microglobulin and may reduce dialysis-related amyloidosis.

Vascular access

Access choice strongly influences morbidity. A native arteriovenous fistula is preferred because it has the lowest infection and thrombosis rates, but requires maturation, commonly 6–12 weeks. Arteriovenous grafts mature faster but have higher stenosis and infection rates. Tunnelled central venous catheters are reserved for urgent or bridging use; they carry major risks of bacteraemia, central venous stenosis and inadequate dialysis. Avoid venepuncture and cannulation in potential fistula arms.

Peritoneal Dialysis

Peritoneal dialysis uses the peritoneal membrane as a semipermeable dialyser. Dialysate glucose generates osmotic ultrafiltration; icodextrin is useful for long dwells and high transporters. Modalities include CAPD, usually 3–5 manual exchanges/day with 1.5–2.5 L dwell volumes, and APD, automated overnight cycling. Adequacy targets include total weekly Kt/V ≥1.7, incorporating residual renal function. PD better preserves residual kidney function and offers autonomy, but is limited by peritonitis, hernias, leaks, protein loss, glucose exposure, and encapsulating peritoneal sclerosis.

Feature	Haemodialysis	Peritoneal dialysis
Solute removal	Intermittent, rapid diffusion ± convection	Continuous, lower intensity
Volume control	Ultrafiltration across dialyser membrane	Osmotic ultrafiltration via glucose/icodextrin
Key infection	Access bacteraemia, especially catheter-related	Peritonitis and exit-site infection
Best suited to	Patients unable to self-manage PD; severe abdominal adhesions; inadequate PD clearance	Autonomy, haemodynamic instability, difficult vascular access
Relative contraindications	No absolute contraindication, but poor vascular access problematic	Extensive adhesions, active inflammatory bowel disease, recurrent diverticulitis, severe hernias

Complications

Intradialytic hypotension is common and reflects excessive ultrafiltration, autonomic dysfunction, impaired cardiac reserve or vasodilatory dialysate temperature; management includes dry-weight reassessment, sodium/fluid restriction, cooler dialysate and reducing ultrafiltration rate. Disequilibrium syndrome results from rapid urea removal causing cerebral osmotic shifts, classically during first dialysis in severe uraemia; prevention is short, low-efficiency initial dialysis. Other HD complications include cramps, arrhythmias from potassium shifts, haemolysis, air embolism, dialyser reactions, access steal syndrome, and dialysis-related amyloidosis.

PD peritonitis is diagnosed when at least two of abdominal pain/cloudy effluent, effluent white cell count >100/µL with >50% neutrophils after dwell, and positive culture are present. Empirical intraperitoneal antibiotics should cover Gram-positive and Gram-negative organisms, for example vancomycin or cefazolin plus ceftazidime or an aminoglycoside, tailored to local protocols and culture results. Refractory, relapsing, fungal or severe peritonitis often requires catheter removal. Long-term dialysis care also requires vaccination, medication dose adjustment, preservation of residual renal function, shared decision-making and timely transplant referral where appropriate.

Renal Transplant

Renal transplantation is the preferred renal replacement therapy for suitable patients with end-stage kidney disease, conferring superior survival, cardiovascular outcomes, fertility, quality of life and cost-effectiveness compared with long-term dialysis. Survival benefit is seen across most age groups, although early peri-operative risk means benefit may be delayed in older or highly comorbid recipients. Pre-emptive transplantation, ideally from a living donor before dialysis initiation, is associated with better graft survival than transplantation after prolonged dialysis exposure.

Assessment, Listing and Donor Selection

Referral for transplant assessment is generally recommended when estimated glomerular filtration rate falls below approximately 20 ml/min/1.73 m² or where progression to kidney failure within 12 months is likely. Absolute contraindications include active malignancy, uncontrolled infection, severe irreversible cardiopulmonary disease, active substance misuse, and inability to adhere to immunosuppression. Relative contraindications include frailty, obesity, severe peripheral vascular disease, poorly controlled psychiatric disease and recurrent disease with high recurrence risk.

Domain	Key MRCP-relevant points
Donor type	Living related/unrelated donors provide best outcomes; deceased donors may be donation after brain death or circulatory death. Expanded-criteria donors increase access but have higher delayed graft function.
ABO compatibility	ABO-compatible transplantation is standard. ABO-incompatible transplantation requires desensitisation with rituximab, plasma exchange or immunoadsorption and carries higher antibody-mediated rejection risk.
HLA matching	HLA-A, -B and -DR matching remains important, especially HLA-DR. Preformed donor-specific anti-HLA antibodies predict hyperacute and antibody-mediated rejection.
Crossmatch	Complement-dependent cytotoxicity crossmatch positivity is usually a contraindication. Flow cytometry and Luminex single-antigen bead assays detect lower-level donor-specific antibodies.

Immunosuppression

Modern regimens use induction plus lifelong maintenance therapy. The aim is to prevent alloimmune injury while minimising infection, malignancy, metabolic toxicity and nephrotoxicity. Induction is typically with basiliximab, an anti-CD25 monoclonal antibody, or lymphocyte-depleting therapy such as antithymocyte globulin in high immunological risk patients.

Drug/class	Typical use and dose	Major toxicities/exam associations
Basiliximab	20 mg IV on day 0 and day 4	Non-depleting IL-2 receptor blockade; low infection risk
Tacrolimus	Usually 0.05–0.1 mg/kg twice daily initially; trough commonly 5–12 ng/ml depending on time post-transplant and risk	Nephrotoxicity, tremor, seizures, hypertension, hyperkalaemia, diabetes, thrombotic microangiopathy; CYP3A4 interactions
Ciclosporin	Approximately 3–5 mg/kg/day in divided doses; trough target varies by protocol	Nephrotoxicity, hypertension, hypertrichosis, gingival hyperplasia, hyperuricaemia
Mycophenolate mofetil	1 g twice daily, or mycophenolic acid 720 mg twice daily	Diarrhoea, leucopenia, teratogenicity; inhibits inosine monophosphate dehydrogenase
Prednisolone	High peri-operative dose then taper; maintenance often 5 mg/day or steroid-minimisation protocols	Diabetes, osteoporosis, infection, weight gain, avascular necrosis
mTOR inhibitors: sirolimus, everolimus	Alternative or CNI-sparing therapy	Mouth ulcers, hyperlipidaemia, impaired wound healing, pneumonitis, proteinuria; possible lower skin cancer risk

The landmark ELITE-Symphony trial supported low-dose tacrolimus plus mycophenolate and corticosteroids as providing superior renal function and lower acute rejection compared with ciclosporin-based regimens. Calcineurin inhibitors remain central but chronic CNI nephrotoxicity contributes to interstitial fibrosis and tubular atrophy.

Rejection: Timing and Pathology

Rejection may present with rising creatinine, oliguria, graft tenderness or hypertension, but is often asymptomatic and detected biochemically. Ultrasound excludes obstruction, vascular compromise and collections, but biopsy is usually required for diagnosis and is classified using Banff criteria.

Type	Timing	Mechanism	Features and treatment
Hyperacute	Minutes to hours	Preformed anti-ABO or anti-HLA antibodies causing complement-mediated endothelial injury	Immediate thrombosis and graft failure; prevented by crossmatch; graft nephrectomy often required
Acute T-cell-mediated	Days to months, but any time with under-immunosuppression	Recipient T-cell recognition of donor alloantigen	Interstitial inflammation, tubulitis, intimal arteritis; treat with IV methylprednisolone 250–500 mg daily for 3 days, antithymocyte globulin if steroid-resistant
Antibody-mediated	Early or late	Donor-specific antibodies, complement activation	Microvascular inflammation, C4d positivity, transplant glomerulopathy; treat with plasma exchange, IVIG, rituximab in selected cases
Chronic allograft dysfunction	Months to years	Immune and non-immune injury including CNI toxicity, hypertension, recurrent disease	Progressive eGFR decline, proteinuria, interstitial fibrosis/tubular atrophy; limited reversibility

Infective, Malignant and Medical Complications

Opportunistic infection risk follows a characteristic timeline: first month is dominated by surgical and donor-derived infection; months 1–6 by opportunistic infection; after 6 months by community infection unless over-immunosuppressed. Cytomegalovirus risk is highest in donor-positive/recipient-negative pairs. Valganciclovir prophylaxis, commonly 900 mg once daily adjusted for renal function for 3–6 months, is standard in high-risk recipients. Pneumocystis jirovecii prophylaxis with co-trimoxazole 480 mg daily or 960 mg three times weekly is usually given for at least 3–6 months and also reduces UTI and nocardiosis. BK polyomavirus causes nephropathy with decoy cells, viraemia and graft dysfunction; management is reduction of immunosuppression rather than antiviral therapy.

Malignancy risk is increased, particularly non-melanoma skin cancer, post-transplant lymphoproliferative disorder associated with Epstein–Barr virus, cervical, vulval, anal and renal tract cancers. Recipients require vaccination before transplantation where possible; live vaccines are contraindicated after transplantation. Cardiovascular disease remains the leading cause of death with a functioning graft, mandating aggressive control of blood pressure, diabetes, lipids, smoking and weight. New-onset diabetes after transplantation is strongly associated with tacrolimus, corticosteroids, obesity, hepatitis C and older age.

Recurrent and De Novo Renal Disease

Several primary renal diseases recur after transplantation. Focal segmental glomerulosclerosis may recur early, sometimes within days, presenting with heavy proteinuria and treated with plasma exchange and intensified immunosuppression. IgA nephropathy commonly recurs histologically but less often causes graft loss. Dense deposit disease and atypical haemolytic uraemic syndrome have high recurrence risk; complement-mediated atypical HUS may require eculizumab. Diabetic nephropathy may recur slowly, whereas anti-GBM disease requires transplantation only after sustained antibody negativity, often at least 6 months.

Graft failure should prompt timely re-referral for dialysis planning or retransplantation. Immunosuppression after graft loss is individualised: withdrawal reduces infection and malignancy risk but increases sensitisation, compromising future transplantation. For MRCP, the key principle is that transplantation is not merely “renal replacement” but a chronic immunological state requiring integrated management of rejection, infection, malignancy, cardiovascular risk and recurrent disease.