Renal Hypertension & Renal Transplant

Renal Hypertension

Renovascular hypertension is hypertension caused by renal ischemia from partial or complete renal-artery occlusion — the most common form of secondary, potentially curable hypertension. Although renal-artery disease affects only a small fraction of hypertensives, it may underlie renal failure in 10–20% of ESRD patients.

Etiology

• Adults — atherosclerosis is the most common cause (60–80%), typically involving the proximal third of the renal artery (often an aortic plaque impinging on the ostium); fibromuscular dysplasia is second (20–40%), involving the distal segments.
• Children — fibromuscular dysplasia, vasculitis, neurofibromatosis, and neuroblastoma.

Pathophysiology

Feature	2-Kidney, 1-Clip (vasoconstrictor)	1-Kidney, 1-Clip (volume)
Driver	RAAS activation → angiotensin II vasoconstriction	Volume expansion and sodium retention
Renin	↑ in the ischemic kidney, suppressed in the normal contralateral kidney	Suppressed (feedback inhibition)
Treatment	ACE inhibitor/ARB, or "unclipping"	Volume management (normal angiotensin II)

In 2K1C, the normal contralateral kidney mounts a natriuresis; in 1K1C, the absence of a normal contralateral kidney prevents that natriuresis, so volume expansion sustains the hypertension even as renin falls.

Ischemic nephropathy — hemodynamically significant RAS damages the whole parenchyma, driven more by proinflammatory mediators than by the drop in renal blood flow alone. A "critical stenosis" is 70–80% (reducing RBF >40%); beyond 80% stenosis, perfusion pressure falls below 70–80 mmHg and the kidney can no longer autoregulate. Renovascular hypertension is most likely with ≥70% stenosis (one or both arteries) or 50% stenosis with post-stenotic dilatation.

Diagnosis and Evaluation

Clinical clues that warrant evaluation: severe/refractory hypertension with grade III–IV retinopathy; abrupt-onset moderate–severe hypertension; onset before age 20 or after 50; unexplained worsening renal function on an ACE inhibitor/ARB; paradoxical worsening with diuretics; recurrent "flash" pulmonary edema; a systolic-diastolic abdominal bruit radiating to the flanks; and diffuse vascular disease/cholesterol embolisation.

• Screening (highest sensitivity/specificity): MRA, CTA, and duplex Doppler US (renal scintigraphy is no longer recommended). CTA and MRA poorly visualise the distal arterial tree. Gadolinium MRA gives both RBF and GFR but is limited by nephrogenic-systemic-fibrosis risk when GFR <30 mL/min; CTA is limited by creatinine >1.7 mg/dL; duplex US relies on a peak systolic velocity >180 cm/s (operator-dependent).
• Confirmatory: angiography (conventional and intra-arterial digital subtraction) remains the gold standard and is indicated when suspicion is high — renovascular disease can be present despite a negative screen, especially with distal/intrarenal lesions.

Fibromuscular Dysplasia

FMD typically affects younger Caucasian women and is usually bilateral, presenting with hypertension, headache, and pulsatile tinnitus.

• Medial fibroplasia — the most common type (70–80%); women 25–50; involves the distal main renal artery; unlikely to progress to occlusion or function loss (the classic "string of beads").
• Intimal fibroplasia — the most common focal type; may cause dissection, mural hematoma, and infarction; likely to progress without intervention.
• Perimedial fibroplasia — 10–25%; younger women (5–15); mid-renal artery; likely to progress.
• Medial hyperplasia — rare; likely to progress.

Surveillance is duplex ultrasound of kidney length and cortical thickness once or twice yearly.

Management

Three options control BP: medical therapy, percutaneous transluminal renal angioplasty (PTRA) ± stenting, and surgery.

• Medical therapy controls BP in >90%; ACE inhibitors/ARBs are particularly effective (the hypertension is renin-driven) but are contraindicated in bilateral RAS. Because they can drop perfusion below the critical level, monitor renal function closely.
• PTRA ± stenting — successful for FMD (restenosis up to 27%) but not for atherosclerotic RAS (the CORAL trial showed no meaningful benefit over medical therapy). For renal-function preservation, PTRA matches surgery for non-ostial lesions, but the ostial lesions that make up 80–85% of atherosclerotic RAS need stenting (plain angioplasty fails).
• Surgical revascularization — indicated for concomitant aortic aneurysm/occlusive disease, a renal-artery macroaneurysm with stenosis, malignant/accelerated hypertension refractory to medical therapy, >75% occlusion (bilateral or solitary kidney), or when PTRA is impossible. Best outcomes need a kidney >8 cm (a kidney <8 cm is end-stage), a patent distal artery with collateral filling, viability on renography, and minimal glomerulosclerosis on biopsy; severe loss (creatinine >4 mg/dL) makes recovery unlikely. With a severely diseased aorta, use a splenorenal bypass on the left or a hepatorenal bypass on the right.
• Renal denervation — endovascular radiofrequency ablation of the renal sympathetics (which run in the arterial adventitia) lowers plasma renin and raises RBF, but the SIMPLICITY trial showed it was unsuccessful for resistant hypertension.

Transplant: Recipient & Donor Selection

Renal transplantation offers significantly better survival than dialysis. This tab covers the ESRD background, recipient selection (disease recurrence, contraindications, and cancer waiting periods), the pre-transplant surgical evaluation, deceased- and living-donor criteria, and ABO/HLA compatibility.

Background

The most common causes of ESRD, in descending order, are diabetes, hypertension, glomerulonephritis, and cystic renal disease. In children, ESRD causes growth failure, poor nutrition, and psychiatric problems. Other points:

• Nephrotic syndrome causes a hypercoagulable state from urinary loss of the natural anticoagulants antithrombin III, protein C, and protein S.
• Patients over 50 have a 20% first-year mortality on dialysis; the most common causes of death in renal failure are heart disease, sepsis, and stroke.
• Phospho-soda enemas are contraindicated in poor renal function (phosphate load), and a calcium × phosphorus product >60 mg²/dL² risks vascular calcification, arterial thrombosis, and calciphylaxis. Peritoneal dialysate containing icodextrin causes falsely high point-of-care glucose readings.

Recipient Selection

Disease recurrence in the graft:

• Recur AND cause secondary graft failure (mnemonic MO-SHAFF): Membranoproliferative GN, primary Oxalosis, Sickle cell disease, Hemolytic-uremic syndrome, Amyloidosis, primary Focal segmental glomerulosclerosis, Fabry disease.
• Recur but rarely cause failure: IgA nephropathy (Berger disease — the most common cause of glomerular hematuria), and hypertension/diabetes (which take years).
• Do NOT recur (mnemonic DACA): renal Dysplasia, ADPKD, Cystinosis, and Alport syndrome (without anti-GBM antibodies).
• Primary oxalosis and other metabolic diseases may warrant a combined kidney–liver transplant.

Absolute contraindications (mnemonic TICCC): unsuitable for Technical success, active Infection, severe Comorbidity (high perioperative mortality), non-Compliance, and active Cancer (a 5-year disease-free interval is generally recommended). Note that low-risk prostate cancer is not a contraindication (ESRD morbidity is greater) — active-surveillance candidates may be transplanted if adherent — while high-risk disease needs definitive treatment first.

Cancer waiting periods (Ontario listing criteria):

Cancer	Waiting period
Bladder	≥2 years (superficial low-grade: often none)
Renal cell	≥2 years (small incidental: none; large/invasive: 5 years)
Testicular, cervical, lung, thyroid	≥2 years
Wilms' tumour	≥1 year
Melanoma	≥5 years (in situ: ≥2 years)
Basal cell	none required
Breast, colorectal	≥5 years (DCIS / localized: ~2 years)
Lymphoma, PTLD, leukemia	≥2 years

(EAU guidelines allow listing low-stage/grade RCC or prostate cancer without additional delay.)

Surgical Evaluation

Careful assessment of the peripheral vascular system is essential. Indications for pre-transplant nephrectomy: symptomatic stones not clearable by minimally invasive means; high-grade solid renal tumours; polycystic kidneys that are symptomatic, extend below the iliac crest, are infected, or harbour tumours; persistent anti-GBM antibody; uncontrolled significant proteinuria; recurrent pyelonephritis; and grade 4–5 reflux with UTIs. Only severe proteinuria can reliably be managed by transcatheter embolization instead. Even small defunctionalised bladders usually regain normal volume within weeks.

The single most important factor for receiving a deceased-donor organ is time on the waiting list. Best outcomes come from pre-emptive transplant just before dialysis is needed; in the US, a GFR <20 mL/min is required to join the national deceased-donor list.

Donor Selection

Donors are declared dead by neurologic criteria (NDD) or circulatory death (DCD). DCD kidneys face variable warm ischemia (risk of delayed graft function) but have long-term survival comparable to NDD.

• Extended-criteria donor (ECD): age ≥60, or 50–59 with ≥2 risk factors (death from stroke, hypertension, or elevated creatinine before recovery). A standard-criteria donor (SCD) is age <60 without those features. ECD organs have a 2-year graft survival of 80% vs 88% for SCD.
• ABO incompatibility — incompatible antibodies bind donor endothelial antigens, triggering complement, thrombosis, and rapid graft loss; transplant is feasible with low antibody titres using plasmapheresis/immunoadsorption (to remove antibody) plus IVIG and anti-CD20 (to prevent reformation), or via paired exchange.
• Histocompatibility — HLA class I (A, B, C) is on all nucleated cells; class II (DR, DQ, DP) is on antigen-presenting cells and endothelium. Pre-formed HLA antibodies arise from pregnancy, prior transplants, transfusions, and some infections; a patient is sensitised at antibodies to 20% of the population and highly sensitised at 80% (the panel-reactive antibody, PRA). The most sensitive test for donor-specific antibody is solid-phase single-antigen bead testing.

Living Donors

Absolute contraindications: age <18, disease that raises the donor's own risk of kidney failure, GFR <60 mL/min, active infection, ongoing substance abuse, and major psychiatric disease. Relative: obesity (ideal BMI <30) and hypertension (some centres accept single-agent-controlled). Urolithiasis is not necessarily a bar — a single small stone with a normal metabolic work-up is acceptable (donate the stone-bearing kidney), but multiple stones/episodes are a contraindication. After donor nephrectomy the donor retains ~75% of total renal function, and hyperfiltration injury has not been a problem.

Transplant: Operation & Post-Transplant Care

This tab covers the donor and recipient operations, early post-transplant complications (urinary and lymphatic leaks, vascular thrombosis, and rejection), allograft nephrectomy, and post-transplant fertility.

Transplant Operation

• Donation — most laparoscopic donor nephrectomies are left-sided (the longer left renal vein eases implantation). Mobilise the ureter only to the iliac-vessel crossing, leaving the gonadal vein and artery to the donor. Hem-o-lok clips are contraindicated on the aortic side of the donor renal artery (associated with living-donor deaths).
• Allograft preparation — ligate renal-vein branches (e.g. the left adrenal vein) and peri-hilar fatty/lymphatic tissue (to prevent lymphocele). The best preservation fluid is University of Wisconsin (UW) solution, and early graft function correlates directly with cold ischemia time.
• Recipient operation — the kidney is placed extraperitoneally in the iliac fossa (minimising ileus, keeping the ureter medial), anastomosed to the external iliac vessels. Keep CVP at 10–15 cmH₂O and MAP >80 mmHg, and avoid the genitofemoral nerve lateral to the external iliac artery. The venous anastomosis is done first (to limit leg ischemia), an IV furosemide + mannitol bolus is given before reperfusion, and urinary continuity is restored by an antireflux ureteroneocystostomy with a routine stent (which reduces ureteral complications).

Post-Transplant Care

The best predictor of immediate graft function after living-donor transplant is the donor kidney's urine output just before nephrectomy. The catheter is usually removed on POD3. Early complications include infection, bleeding, urinary leak, lymphocele, vascular thrombosis, and rejection.

• Urinary leak — presents with falling catheter output and rising drain output; replace the catheter immediately if it was already removed. Most heal with the stent and catheter drainage; non-healing leaks need a nephrostomy or open repair.
• Lymphocele — arises from the graft or peri-iliac lymphatics (reduced by a closed-suction drain removed when output is <50 mL/day). Large ones cause pain, infection, or graft compression; manage by a stepwise ladder of image-guided aspiration → closed-suction drain → sclerosant → peritoneal window.
• Vascular thrombosis — renal-artery thrombosis (within 3 days; from a hypercoagulable state or delayed graft function) presents with sudden cessation of urine output and no flow on Doppler; renal-vein thrombosis follows hypercoagulability, kinking/stenosis, rejection, or hypotension. For both, emergent thrombectomy/thrombolysis is attempted but rarely successful.
• Elevated resistive index (normal RI = 0.60–0.70) has many causes (mnemonic ARVOCAD): renal Artery stenosis, Rejection, renal Vein thrombosis, ureteric Obstruction, perinephric Collection, ATN, and Drug toxicity.
• Rejection:
  • Hyperacute (humoral) — minutes after reperfusion; recipient cytotoxic antibodies and complement attack donor endothelium → thrombosis. Now rare thanks to sensitive crossmatching.
  • Acute — classically ~5 days post-transplant (without immunosuppression); rising creatinine and falling urine output, with needle biopsy the diagnostic standard.
  • Chronic — gradual decline with interstitial fibrosis, arteriolar sclerosis, and tubular atrophy that rarely improve with more immunosuppression.

Allograft Nephrectomy and Fertility

Allograft nephrectomy is technically challenging and reserved for specific situations; removing a graft that fails within the first year can lower anti-HLA antibodies and ease re-transplantation. Fertility usually recovers after successful transplant — FSH, LH, and testosterone normalise and spermatogenesis improves in men (with no increase in offspring abnormalities, though impregnation should be delayed ≥1 year), and fertility is restored in premenopausal women. Haemorrhagic cystitis in an immunosuppressed patient is most often due to adenovirus.

Transplant: Immunosuppression

Modern immunosuppression has improved early graft survival but has had little impact on late graft loss, which is largely driven by chronic rejection. This tab covers the mechanisms of the immunosuppressive agents, infection prophylaxis and drug interactions, and the malignancy risk of chronic immunosuppression.

Mechanisms of Immunosuppressants

Agent	Mechanism of action
Glucocorticoids	Reduce transcription of cytokine genes
Azathioprine, mycophenolate mofetil	Inhibit purine synthesis
Sirolimus, everolimus	Inhibit cell-cycle progression (mTOR inhibitors)
Tacrolimus, cyclosporine	Inhibit calcineurin → reduce IL-2 production
Basiliximab	Blocks the IL-2 receptor
Antithymocyte globulin	Depletes T lymphocytes
Rituximab	Depletes B lymphocytes
Alemtuzumab	Depletes T and B lymphocytes
Belatacept	Costimulation blockade
Bortezomib	Proteasome inhibitor
Eculizumab	Complement inhibitor

Corticosteroids most impair wound healing, and prednisone, cyclosporine, and sirolimus all cause hyperlipidemia.

Infection Prophylaxis and Drug Interactions

• Prophylaxis — TMP-SMX for 3 months against Pneumocystis pneumonia, and ganciclovir, acyclovir, valacyclovir, or CMV immune globulin against cytomegalovirus.
• CYP450 metabolism — cyclosporine and tacrolimus are metabolised by cytochrome P450, so doses must be adjusted with interacting drugs (e.g. fluconazole, ketoconazole). Diltiazem and ketoconazole are sometimes used deliberately to reduce calcineurin-inhibitor dosing and cost while maintaining levels.
  • P450 inducers (lower calcineurin-inhibitor levels): barbiturates, phenobarbital, phenytoin, carbamazepine, rifampin, griseofulvin, sulfonylureas, St. John's wort, and chronic alcohol.
  • P450 inhibitors (raise levels): valproate, isoniazid, cimetidine, ketoconazole, fluconazole, sulfonamides, chloramphenicol, erythromycin (macrolides except azithromycin), amiodarone, omeprazole, quinidine, grapefruit juice, and acute alcohol.

Malignancy Risk

Chronic immunosuppression raises cancer risk, and skin cancer is the most common malignancy after solid-organ transplant. Several virus-associated cancers are increased — Kaposi sarcoma (HHV-8), non-Hodgkin lymphoma (EBV), vulvar cancer (HPV), and hepatocellular carcinoma (hepatitis C) — as are kidney, penile, and bladder cancers. (For contrast: HIV raises kidney, penile, and testis cancer risk, and metabolic syndrome raises kidney, bladder, and prostate risk.) Notably, prostate cancer incidence is decreased in transplant recipients, and lymphoma may respond to reducing immunosuppression.