Kidney Cancer: Symptoms, Stages, and Treatment

What Is Kidney Cancer?

The kidneys are a pair of organs on either side of the spine in the lower back. They filter waste from the blood to produce urine and regulate fluid-electrolyte balance and blood pressure. Renal cell carcinoma most often arises from the kidney's urine-producing tubular cells. Early disease generally remains within the kidney capsule; as it progresses, it can spread (metastasize) to nearby structures (the renal vein and inferior vena cava), regional lymph nodes, and distant organs through the bloodstream (such as the lungs, bones, liver, and brain).

How Common Is Kidney Cancer? (Current Statistics)

Risk Factors

The main factors shown to contribute to kidney cancer development are:

• Smoking: Smokers have an approximately 38% higher risk than nonsmokers (meta-analysis of 24 studies), with risk increasing in proportion to the amount smoked (approximately 2 times the risk in people smoking more than 40 cigarettes daily).
• Obesity: Each unit increase in body mass index (BMI) increases risk by approximately 5-7%; people with BMI ≥35 have an approximately 71% higher risk than those of normal weight.
• Hypertension (high blood pressure): Risk increases progressively with systolic blood pressure (~1,7 times in the 130-149 mmHg range, ~2 times at ≥170 mmHg); this association has also been demonstrated independently of obesity.
• Chronic kidney failure and dialysis (acquired cystic kidney disease): In patients on long-term dialysis, acquired cystic disease of the kidneys is reported to substantially increase kidney cancer risk compared with the general population (by several tens of times in the literature).
• Occupational exposure — trichloroethylene: Occupational exposure to trichloroethylene, used as an industrial solvent, increases risk by approximately 26-35%; IARC classifies it as a definite human carcinogen (Group 1).
• Hereditary (inherited) syndromes: Approximately 70% of people with von Hippel-Lindau (VHL) disease develop kidney cancer by age 60. In hereditary leiomyomatosis and renal cell cancer (HLRCC), cumulative risk by age 85 is approximately 21%, generally presenting at a younger age (median in the 30s) with an aggressive course. In tuberous sclerosis complex, lifetime risk is approximately 2-3%. Increased risk has also been demonstrated in Birt-Hogg-Dubé syndrome, although a precise lifetime risk is not clearly established in the literature.
• Family history: Kidney cancer in first-degree relatives approximately doubles the risk (2 times).

Types of Kidney Cancer (Histological Classification)

According to the World Health Organization (WHO) 5th edition classification updated in 2022, renal cell carcinoma is a group of diseases with different genetic/molecular characteristics and treatment responses rather than a single disease:

What Are the Symptoms?

The clinical presentation of kidney cancer has changed significantly in recent years. According to current data cited in the European Association of Urology (EAU) guideline, approximately 60% of cases are now detected incidentally during abdominal/lower-back imaging for another reason, when the patient has no symptoms. This proportion rises to approximately 87% for small tumors (T1a, ≤4 cm) and falls to 39% for advanced (III-IV) disease — symptomatic presentation therefore still correlates with more advanced disease.

Nevertheless, assessment is needed if one or more of the following signs and symptoms occur:

• Blood in the urine visible to the eye or detected on testing (hematuria)
• Persistent pain in the lower back or flank (costovertebral angle)
• A palpable abdominal mass
• Unexplained weight loss
• Persistent fatigue and weakness
• Loss of appetite
• Unexplained, recurrent fever
• Night sweats
• Anemia (low red blood cells) or, conversely, erythrocytosis (excess red blood cells)
• Leg swelling (may reflect major venous involvement in advanced cases)

How Is It Diagnosed?

When a kidney mass is suspected, diagnosis generally proceeds through these steps:

• Imaging: Abdominal ultrasound may be the starting point; contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) is used for definitive characterization. These assess the mass's size, solid/cystic structure, contrast enhancement, and spread to adjacent structures (renal vein, vena cava, lymph nodes).
• Biopsy: Not mandatory for every patient, but a percutaneous (needle) biopsy may be performed if the diagnosis is uncertain, for small masses planned for active surveillance, or when histological confirmation is needed before systemic treatment.
• Staging imaging: Chest X-ray or chest CT assesses distant metastases (most commonly in the lungs); bone scintigraphy or brain imaging is added if symptoms or laboratory findings warrant it.
• Laboratory tests: A complete blood count (anemia/erythrocytosis), kidney function tests, corrected calcium, and liver function tests are needed both for general assessment and for the IMDC risk classification described below.

Staging: The TNM System (AJCC 8th Edition)

Kidney cancer is staged using the internationally accepted TNM system . Although some cancers, such as lung cancer, have recently moved to a new staging edition, the situation for kidney cancer differs:

Grading: The WHO/ISUP System

In addition to stage, the microscopic appearance of tumor cells provides prognostic information. Defined by the 2012 Vancouver ISUP consensus and replacing the older Fuhrman system, WHO/ISUP grading assigns grades from 1 to 4 according to nuclear features (Grade 4 is the most aggressive, including marked nuclear pleomorphism, giant cells, and/or rhabdoid/sarcomatoid differentiation). It applies to clear cell and papillary RCC ; chromophobe RCC is not graded using this system, because the nuclear atypia naturally present in this subtype does not correlate with prognosis as it does in the other subtypes.

Prognostic Factors: The IMDC Risk Classification

Treatment selection in metastatic (advanced) kidney cancer is largely based on the IMDC (International Metastatic RCC Database Consortium) risk classification. It divides patients into three risk groups according to how many of the following 6 factors they have:

Treatment of Localized (Early-Stage) Disease

The Surgical Approach

Surgery is the main treatment for localized kidney cancer. When technically feasible, particularly for T1 tumors (≤7 cm), kidney-sparing partial nephrectomy (removal of part of the kidney) is preferred, because it preserves kidney function better, to radical nephrectomy (complete removal of the kidney). These operations are now frequently performed robotically or laparoscopically (through small incisions); a meta-analysis of 4.919 patients showed that robotic partial nephrectomy provided shorter warm ischemia time, fewer overall complications, and fewer positive surgical margins than the laparoscopic approach.

Routine lymph node dissection is no longer recommended for patients without clinically suspected lymph node involvement (cN0); EORTC 30881 showed occult lymph node involvement in only 3,3% of these patients and no survival advantage from routine dissection. Lymph node dissection is performed only when imaging reveals suspicious nodes, for staging/prognostic purposes.

Active Surveillance and Ablation

For small (generally <3-4 cm), low-complexity kidney masses, particularly in older patients, those with comorbidities, or those at high surgical risk, active surveillance or thermal ablation (cryoablation or radiofrequency ablation) may be considered. The DISSRM registry showed similar medium- to long-term overall and cancer-specific survival with active surveillance versus surgery in well-selected patients. A meta-analysis comparing ablation techniques (1.375 lesions) reported less local progression with cryoablation than with radiofrequency ablation (5,2% versus 12,9%) and less need for retreatment (1,3% versus 8,5%). Nevertheless, surgery (partial nephrectomy) remains the gold standard for 5- and 10-year cancer-specific survival (~92% and ~80%, respectively).

Postoperative (Adjuvant) Systemic Treatment

Follow-up after nephrectomy includes chest and abdominal imaging (CT/MRI) at intervals determined by recurrence risk: less frequently for low risk and more frequently for 5 years for high risk.

The Role of Surgery in Metastatic Disease: Cytoreductive Nephrectomy

In metastatic kidney cancer, removal of the kidney containing the primary tumor despite the disease having spread (cytoreductive nephrectomy) was standard practice for decades. Studies in the cytokine (interferon) era showed a survival contribution. With targeted treatments, however, this assumption was challenged and became one of the field's most controversial issues.

Oligometastatic Disease: Local Treatments for Limited Spread

A distinctive feature of kidney cancer is that, in some patients, metastases remain limited to a few sites and progress slowly (oligometastatic disease). In these patients, local treatment of metastatic sites, in addition to systemic treatment or sometimes instead of it, can provide long-term disease control — and even long periods without treatment in some patients.

Metastasectomy (Surgical Removal of Metastases)

Particularly in patients with a limited number of lung metastases and a long disease-free interval since nephrectomy (metachronous disease), surgical removal of all metastases has been associated with long survival. However, it is important to be candid: no randomized trial has tested metastasectomy in kidney cancer. All evidence is retrospective and observational. It is therefore impossible to determine precisely how much of the observed survival advantage comes from surgery itself and how much from the inherently better prognosis of patients considered suitable for it (selection bias). Nevertheless, guidelines recommend metastasectomy for selected patients when complete resection is possible.

Stereotactic Radiotherapy (SBRT)

Managing Bone Metastases

When kidney cancer metastasizes to bone, "skeletal-related events" such as fractures, spinal cord compression, and pain can seriously impair quality of life. To reduce these events, bone-protective agents such as denosumab or zoledronic acid are used; current meta-analyses suggest a slight advantage for denosumab over zoledronic acid. An evidence gap should also be noted: there is no randomized trial testing these agents exclusively in kidney cancer patients; the data come from subgroup analyses of mixed-tumor trials. Nevertheless, current real-world data show these agents are substantially underused in metastatic kidney cancer — an overlooked supportive care opportunity. Use requires monitoring of kidney function, dental assessment for jaw osteonecrosis risk, and calcium/vitamin D supplementation. In choosing systemic treatment for patients with bone metastases, cabozantinib is frequently preferred because of its activity at these sites.

Systemic Treatment of Metastatic (Advanced) Disease

Treatment decisions in clear cell kidney cancer with distant metastases depend on the IMDC risk group described above. Over the past 10 years, treatment has changed fundamentally from targeted drugs alone to immunotherapy-based combinations.

First-Line Treatment: FDA-Approved Combinations

In suitable, selected favorable-risk patients — for example, those with comorbidities, those wishing to reduce medication burden, or those for whom additional combination toxicity may outweigh the benefit — single-agent VEGFR-TKIs such as sunitinib or pazopanib remain reasonable, guideline-accepted options. NCCN and particularly ESMO list this approach as an alternative to combinations in favorable-risk disease. There is no direct comparative trial demonstrating superiority among the four combinations (nivolumab+ipilimumab, pembrolizumab+axitinib, nivolumab+cabozantinib, pembrolizumab+lenvatinib), so current NCCN and ESMO guidelines do not prefer one over another. Choice depends on individual factors such as tumor burden, symptoms, comorbidities, and the possibility of a lasting treatment-free response (observation without treatment after complete response).

HIF-2α Inhibitor: Belzutifan

Although first-line belzutifan combined with cabozantinib (LITESPARK-003) produced promising phase 2 results (overall response rate 70%), it remains investigational and has not received FDA approval.

What Comes After First-Line Immunotherapy?

Second-Line and Subsequent Treatments

The main drugs used in patients resistant to or intolerant of first-line treatment, with their pivotal trial data, are:

Most of these drugs have shifted toward the third line and beyond because first-line treatment is now predominantly immunotherapy-based combinations. The oncologist individualizes drug sequencing according to response to previous treatments and the side-effect profile.

Treatment of Non-Clear Cell RCC

Evidence for papillary, chromophobe, and other rare subtypes is more limited than for clear cell RCC, but important data have accumulated in recent years:

In HLRCC-associated (FH-deficient) papillary RCC, bevacizumab + erlotinib has produced notable results (NEJM, 2024): overall response rate was reported as 72% in HLRCC-associated cases and 35% in sporadic papillary RCC. Collecting duct carcinoma is generally treated with platinum-based chemotherapy (gemcitabine-cisplatin) because of biology resembling urothelial (bladder) cancer, and has a poor prognosis. Associated with sickle-cell trait and SMARCB1 loss, renal medullary carcinoma has a very aggressive course. Chemotherapy regimens such as gemcitabine+doxorubicin can achieve limited responses, and referral to experienced centers and clinical trials is recommended for this rare subtype.

Global Approval and Evidence Timeline

Kidney cancer is one of oncology's fastest and most fundamentally changing treatment fields. In 1992, the sole option was high-dose interleukin-2, effective in only a small proportion of patients and potentially requiring intensive care. Today there are four first-line combinations with proven overall survival benefit, two adjuvant options, and an entirely new drug class (HIF-2α inhibitors). The timeline below summarizes this transformation using FDA approval dates.

Treatment Side Effects and Their Management

VEGFR-TKIs (Sunitinib, Pazopanib, Axitinib, Cabozantinib, Lenvatinib, Tivozanib)

Common side effects of this drug class include hypertension (requiring regular blood pressure monitoring and antihypertensive treatment if needed), hand-foot syndrome (redness, peeling, and pain on the palms and soles), diarrhea, fatigue, hypothyroidism and proteinuria (protein loss in urine). With cabozantinib, the rare but potentially serious risks of gastrointestinal perforation and fistula and, around surgery, delayed wound healing require stopping the drug for a specified interval before planned surgery.

Immunotherapy Drugs (Nivolumab, Ipilimumab, Pembrolizumab, Avelumab)

"Immune-related adverse events" (irAEs) caused by excessive activation of the immune system can affect almost any organ: colitis (diarrhea, abdominal pain), hepatitis, pneumonitis, endocrine disorders (thyroiditis, hypophysitis, adrenal insufficiency — generally permanent and requiring lifelong hormone replacement), and skin reactions may occur. With ipilimumab combinations, these side effects may be more frequent and severe than with PD-1/PD-L1 inhibitors alone. Management is grade-based: mild effects allow continuation with close observation; moderate-severe effects require stopping the drug and starting corticosteroids.

Belzutifan-Specific Side Effects

Because belzutifan inhibits HIF-2α and suppresses erythropoietin production, its characteristic side effects differ from those of other drug classes: anemia occurs in the great majority of patients (some may need blood transfusions or support with erythropoiesis-stimulating agents), and hypoxia (low blood oxygen; requiring regular oxygen saturation monitoring and dose adjustment if necessary) is a distinctive effect requiring attention.

Diagnosis, Licensing, and Reimbursement in Türkiye

Kidney cancer diagnosis and treatment in Türkiye are provided in oncology/urology centers at university and teaching-research hospitals in accordance with international guidelines. Drug use first requires licensing by TİTCK (Turkish Medicines and Medical Devices Agency); coverage by SGK (Social Security Institution) additionally requires a reimbursement decision under SUT (Health Implementation Communiqué).

Frequently Asked Questions

Can kidney cancer be cured if detected early?

Yes. Patients diagnosed incidentally at an early stage (Stage I) and treated surgically have a high 5-year relative survival rate of about 93%. Prompt assessment of small kidney masses found incidentally on imaging is therefore important.

How does removal of a kidney (nephrectomy) affect life?

A healthy person can generally maintain daily life with one kidney without difficulty; the remaining kidney compensates by increasing function somewhat over time. Nevertheless, regular monitoring of kidney function through blood tests is recommended, and kidney-sparing (partial) surgery is preferred whenever possible.

Which drug is used first in metastatic kidney cancer?

There is no single standard; the oncologist individualizes choice according to IMDC risk, tumor burden, symptoms, and general health. Guidelines express no clear preference among the four immunotherapy-based combinations with proven overall survival benefit.

Can everyone receive immunotherapy combined with targeted treatment?

No. General health, coexisting autoimmune conditions, organ function, and IMDC risk affect treatment choice; eligibility must be assessed by an oncologist.

Is removing the kidney meaningful when the disease has spread?

This question once automatically received a "yes," but now depends on the circumstances. CARMENA showed that immediate surgery in intermediate/poor-risk patients needing urgent systemic treatment provides no benefit, with numerically better results in the nonsurgical arm. Surgery remains meaningful for patients in good general health, with a low metastatic burden, or with a good systemic-treatment response leaving predominantly the kidney tumor. The decision is multidisciplinary and often made after systemic treatment starts.

I have a complete response. Can I stop treatment?

Kidney cancer is one of the few metastatic cancers where this question genuinely arises. In some patients achieving complete response, particularly with nivolumab+ipilimumab, the response can persist long after treatment stops; at 42 months in CheckMate 214, approximately 18-19% were alive and receiving no treatment. However, this decision is entirely individual and requires close imaging follow-up. Do not stop treatment on your own; plan it together with your oncologist.

Can immunotherapy be given again after first-line immunotherapy?

According to current evidence, no. Two large phase 3 trials, CONTACT-03 and TiNivo-2, showed that adding a new PD-1/PD-L1 inhibitor after progression on immunotherapy provided no benefit and only additional side effects. Treatment at this stage generally continues with VEGFR-TKIs.

Kidney cancer runs in my family. Should I have genetic testing?

Genetic counseling is recommended for people diagnosed young (generally under 45-46), those with bilateral or multifocal kidney tumors, multiple kidney cancers in the family, or other signs of hereditary syndromes (such as skin lesions, lung cysts, eye/brain hemangioblastoma, or multiple uterine fibroids). When VHL, HLRCC, Birt-Hogg-Dubé, or tuberous sclerosis is identified, regular imaging of the patient and family members allows tumors to be detected very early, at a stage suitable for kidney-sparing surgery.